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Detecting and managing hereditary colorectal cancer syndromes in your practice
Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.
Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.
Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:
- Early age of onset of cancer (eg, colorectal cancer before age 50)
- More than 10 colorectal adenomas
- Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
- Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
- A family member with a known hereditary colorectal cancer syndrome (Table 1).
Any of these red flags should prompt a referral for genetic counseling.
SYNDROMES ARE CLASSIFIED AS WITH OR WITHOUT POLYPOSIS
Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).
These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.
In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.
LYNCH SYNDROME (HEREDITARY NONPOLYPOSIS COLORECTAL CANCER)
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.
Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.1 The median age at onset is 45 years.1 For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.2
Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.1
Other extracolonic cancers in Lynch syndrome include cancers of the:
- Stomach (1%–10% risk by age 70 years)
- Ovaries (1%–20% risk)
- Hepatobiliary tract (1%–2% risk)
- Urinary tract (1%–12% risk)
- Small bowel (1%–2% risk)
- Brain (1%–8% risk)
- Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).1,3,4
Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.
Genetics of Lynch syndrome
Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.5 These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.
These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.6
In whom should Lynch syndrome be suspected?
Lynch syndrome can be suspected on the basis of family history and clinical criteria.
In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it1:
- At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
- At least two successive generations involved
- At least one of the cancers diagnosed before age 50
- Familial adenomatous polyposis is excluded.
Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.7 In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).8
Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.
Diagnosis of Lynch syndrome
The diagnosis of Lynch syndrome is based on molecular pathologic analysis (performed on tumor samples) and confirmed by genetic testing.
Molecular pathologic evidence of Lynch syndrome includes microsatellite instability and loss of expression of one or more of the DNA mismatch repair proteins (detected using immunohistochemistry) (more on these below). The revised Bethesda guidelines (TABLE 3) were intended to identify individuals whose tumors should be tested for one or both of these phenomena.9
In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended that all patients with newly diagnosed colorectal cancer undergo microsatellite instability analysis, immunohistochemistry testing, or both, regardless of whether they meet the Amsterdam II or the Bethesda guideline criteria.10
Microsatellite instability analysis. Microsatellites are short sequences of repeated DNA. The tumor cells of patients who carry defective mismatch repair genes have microsatellites that are longer or shorter than in normal cells, a condition called microsatellite instability (ie, “MSI-high”).
Microsatellite instability testing, using a standardized panel of five DNA markers, is performed on normal and tumor tissue. If more than two of the five microsatellite markers in the tumor show instability, the lesion is considered to have a high level of microsatellite instability. About 15% of colorectal cancers have this high level, although most are not associated with Lynch syndrome and lose MLH1 expression by promoter methylation.11,12
While only 2% of patients with colorectal cancer have Lynch syndrome, from 90% to 95% of colorectal cancers from patients with Lynch syndrome have high levels of microsatellite instability.10 The presence of MLH1 promoter hypermethylation, the BRAF mutation V600E, or both within the tumor suggests that the cancer is not associated with Lynch syndrome.
Some families that meet the Amsterdam I criteria have microsatellite-stable tumors: their condition has been called familial colorectal cancer type X.13 This condition is associated with a higher risk of colorectal cancer but not the other malignancies observed in Lynch syndrome.
Immunohistochemistry is performed to assess for expression of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2. Absence of expression of the specific protein within tumor cells compared with normal cells within the specimen suggests dysfunction of the specific gene and guides germline mutation testing (Figure 1). For example, a patient who lacks expression of the MSH2 protein in his or her colon cancer most likely has a mutation in the MSH2 gene. Therefore, germ-line genetic testing should initially target the MSH2 gene. Approximately 88% of Lynch syndrome-associated colorectal cancers have abnormal immunohistochemical staining.10
Testing for microsatellite instability and mismatch repair gene expression ideally precedes germline genetic testing and helps to guide which gene or genes should be tested.9,14
Genetic testing for Lynch syndrome is routinely performed on a blood or saliva sample, using DNA from white blood cells and sequencing the gene or genes involved to look for mutations. Positive results from a germline genetic test confirm the diagnosis of Lynch syndrome and allow for predictive testing for relatives at risk. The term Lynch syndrome is used exclusively to describe individuals with evidence of a mutation in one of the mismatch repair genes.15
If a patient’s results are positive, genetic counseling and genetic testing should be offered to at-risk relatives age 18 and over.
Management of Lynch syndrome
Aggressive cancer surveillance is essential for people with Lynch syndrome and for those who are considered at risk but have not pursued genetic testing, such as a sibling of a person with Lynch syndrome.
Colorectal cancer. Colonoscopy is recommended every 1 to 2 years beginning at the age of 20 to 25 years, or 2 to 5 years earlier than the age of the youngest relative affected with colorectal cancer if the initial diagnosis was before age 25. When patients turn 40 years old, colonoscopy is done annually.16–18 A significant reduction in cancer incidence and in the mortality rate has been shown with colonoscopic surveillance.19–21
Chemoprevention may also have a role. Patients with Lynch syndrome who took aspirin 600 mg per day for an average of 25 months had a significantly lower incidence of colorectal cancer during a 55-month follow-up period compared with patients randomized to placebo.22
For patients with Lynch syndrome who are diagnosed with colorectal cancer, the high risk of metachronous cancers after standard segmental colectomy calls for a more extended resection. Retrospective analysis of 382 Lynch syndrome patients found that none of the 50 who underwent total or subtotal colectomy were diagnosed with metachronous colorectal cancer, whereas a metachronous cancer developed in 74 (22%) of the 332 patients who had had segmented resection.2 Annual surveillance of the remaining colon, rectum, or both is indicated postoperatively.
Gynecologic cancers. Women with Lynch syndrome should also consider gynecologic surveillance and risk-reducing surgery. This includes annual gynecologic examination, transvaginal ultrasonography, and endometrial aspiration, beginning at age 30 to 35 years. Although this surveillance does detect premalignant lesions and early symptomatic cancers, its effect on the mortality rate is unknown. Hysterectomy with bilateral salpingo-oophorectomy has been shown to significantly reduce endometrial and ovarian cancers in women with Lynch syndrome.23,24
Urothelial cancers. Carriers of MSH2 mutations have a significantly higher risk of urothelial cancers.4 Therefore, MSH2 carriers should consider ultrasonography of the urinary tract, urinary cytology, and urinalysis every 1 to 2 years beginning at age 40.4
Other extracolonic cancers. Poor evidence exists for systematic screening for the other extracolonic tumors associated with Lynch syndrome. However, the National Comprehensive Cancer Network advises considering esophagogastroduodenoscopy with extended duodenoscopy as well as capsule endoscopy every 2 to 3 years beginning at age 30 to 35.14
ADENOMATOUS POLYPOSIS SYNDROMES
Familial adenomatous polyposis and MYH-associated polyposis are the next most common hereditary colorectal cancer syndromes. Each of these accounts for about 1% of cases of colorectal cancer. Clinically, these two syndromes can be challenging to distinguish because they overlap phenotypically to a significant degree.
FAMILIAL ADENOMATOUS POLYPOSIS
Familial adenomatous polyposis is caused by mutations in the APC gene. Its prevalence is 2.29 to 3.2 per 100,000 individuals.25,26
Genetics of familial adenomatous polyposis
APC is the only gene known to cause familial adenomatous polyposis. Mutations in APC are inherited in an autosomal dominant manner. Approximately 25% of cases of familial adenomatous polyposis are due to a de novo mutation in APC.27
Clinical presentation of familial adenomatous polyposis
Familial adenomatous polyposis is classified by the burden of colorectal adenomas.
Patients who have fewer than 100 adenomas have an attenuated form of the disease. In this group, polyps usually begin to form in the late teenage years or early 20s and tend to develop in the proximal colon. The attenuated form is associated with an approximately 70% lifetime risk of colorectal cancer.28
Patients who have more than 100 polyps are considered to have the classic form of the disease, and those with more than 1,000 polyps have profuse familial adenomatous polyposis (Figure 2). In these groups, polyps typically begin to develop in the preteenage to mid-teenage years. Without surgery, there is nearly a 100% risk of colorectal cancer. The average age at diagnosis of colorectal cancer is 39 years for patients with classic disease.
Upper gastrointestinal polyps are common in familial adenomatous polyposis. Nearly 90% of patients develop duodenal adenomas by a mean age of 44, with a cumulative lifetime risk of nearly 100%.29 Fundic gland polyposis occurs in nearly 90% of patients,30 while gastric adenomas are reported in fewer than 15% of patients.
Duodenal and periampullary cancer is the second most common malignancy in familial adenomatous polyposis. The lifetime risk ranges from 2% to 36%, depending on the Spigelman stage. People with Spigelman stage I, II, or III have a 2.5% risk of duodenal cancer, while those with stage IV disease have up to a 36% lifetime risk.
Gastric cancer, arising from fundic gland polyps, has been reported but is rare in Western populations.
In familial adenomatous polyposis, the incidence of jejunal adenomas and cancer is less than 10%, and the risk of ileal adenomas and cancer is less than 1%.31
Familial adenomatous polyposis is also associated with a higher risk of other malignancies, including:
- Pancreatic cancer (2% lifetime risk)
- Thyroid cancer (2% to 3% lifetime risk, typically papillary carcinoma)32
- Hepatoblastoma (1% to 2% lifetime risk)
- Brain tumors (< 1% lifetime risk)
- Biliary cancer (higher risk than in the general population).33
Benign extracolonic manifestations that have been observed include osteomas, dental abnormalities (supernumerary teeth, unerupted or absent teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium, benign cutaneous lesions (epidermoid cysts and fibromas), and desmoid tumors.33 The term “Gardner syndrome” has been used to describe patients who have familial adenomatous polyposis but also have osteomas and soft-tissue tumors.34 These patients carry the same risk of colorectal cancer as other patients with familial adenomatous polyposis.
Diagnosing familial adenomatous polyposis
The diagnosis of familial adenomatous polyposis is suspected when a patient has more than 10 adenomatous polyps.
Seventy-five percent of patients with familial adenomatous polyposis have a family history of the condition. Therefore, most cases are identified at a young age on screening sigmoidoscopy or colonoscopy or by predictive gene testing. Patients rarely have cancer at the time of diagnosis.
The other 25% of patients typically are diagnosed when symptoms develop from the polyps or cancer. Over 50% of these symptomatic patients have cancer at the time of diagnosis.
It is recommended that people who have more than 10 adenomas detected on a single colonoscopy or who are first-degree relatives of patients with familial adenomatous polyposis undergo a genetic evaluation and testing for mutations in the APC gene.14 Once an APC mutation is identified in the family, at-risk relatives should be offered testing around age 10 years for families with classic familial adenomatous polyposis or in the mid to late teenage years for those with the attenuated form. It also appropriate to refer patients with desmoid tumors, duodenal adenomas, and bilateral or multifocal congenital hypertrophy of the retinal pigment epithelium for a genetic evaluation.
Management of familial adenomatous polyposis
Flexible sigmoidoscopy every 1 to 2 years beginning at age 10 to 12 years is recommended for individuals and families who have been phenotypically or genetically diagnosed with familial adenomatous polyposis.35–37 If colorectal adenomas are found, surgical options should be discussed and annual colonoscopic surveillance should commence.
For people with the attenuated form, because of the later age of disease onset and the tendency for right-sided disease, colonoscopy every 1 to 2 years should commence at about age 18.35–37 If polyps are found, colonoscopy should be performed every year.
The decision of when to offer colectomy is based on polyp burden (taking into account the number, pathologic appearance, and size of the polyps) and psychosocial factors such as patient maturity. Surgical options include total colectomy and ileorectal anastomosis or total proctocolectomy and ileal pouch anal anastomosis.38 Colonic and extracolonic phenotype as well as genotype should factor into the type of operation recommended. After colectomy, annual endoscopic surveillance of the rectum or ileal pouch is indicated to screen for recurrent polyposis and cancer.
Chemoprevention with sulindac (Clinoril) 150 mg or celecoxib (Celebrex) 400 mg twice a day causes regression of colorectal adenomas in familial adenomatous polyposis and may be useful as an adjunct to endoscopy in managing the colorectal polyp burden.39,40
Forward and side-viewing upper endoscopy should commence at age 20. This should include visualization and biopsy of the papilla and periampulllary region.29 The frequency of endoscopic surveillance depends on the Spigelman stage, which reflects the duodenal polyp burden. It is recommended that patients with Spigelman stage IV duodenal polyposis be seen in consultation with an experienced gastrointestinal surgeon for consideration of a prophylactic, pylorus-preserving, pancreas-sparing duodenectomy. This procedure has been shown to be more effective in polyp control and cancer prevention than endoscopic polyp ablation and local surgical resection.41
Some evidence for the utility of celecoxib 400 mg twice daily for the regression of duodenal polyposis was noted in a 6-month placebo-controlled trial.42 Some experts recommend removal of large duodenal adenomas, with adjunctive celecoxib therapy to control polyposis burden.30
People with familial adenomatous polyposis have been shown to have a 2.6% risk of thyroid cancer, and ultrasonography of the neck with attention to the thyroid is recommended for them.32
MYH-ASSOCIATED POLYPOSIS
Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.
Genetics of MYH-associated polyposis
MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.43 These two mutations are estimated to occur in 1% to 2% of the general population.44
Clinical presentation of MYH-associated polyposis
MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.48 Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.49 Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.49
Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.50,51
Diagnosis of MYH-associated polyposis
Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. 14 It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.52 The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.
Management of MYH-associated polyposis
The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.14 Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.49
GENETIC COUNSELING AND GENETIC TESTING
The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.16 They further recommend genetic counseling and informed consent before genetic testing.16
Genetic counseling is a process of working with patients and families whereby:
- A detailed medical and family history is obtained
- A formal risk assessment is performed
- Education about the disease in question and about genetic testing is provided
- Psychosocial concerns are assessed
- Informed consent is obtained when genetic testing is recommended.53
This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.
In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.54 In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.
When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.
Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.
Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.
- Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011; 305:2304–2310.
- Parry S, Win AK, Parry B, et al. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 2011; 60:950–957.
- Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 2009; 75:141–149.
- van der Post RS, Kiemeney LA, Ligtenberg MJ, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet 2010; 47:464–470.
- Wijnen JT, Vasen HF, Khan PM, et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998; 339:511–518.
- Bisgaard ML, Bernstein I. HNPCC mutation rate. Familial Cancer 2003; 2.
- Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991; 34:424–425.
- Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999; 116:1453–1456.
- Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004; 96:261–268.
- Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Genet Med 2009; 11:15–20.
- Aaltonen LA, Peltomäki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993; 260:812–816.
- Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994; 145:148–156.
- Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293:1979–1985.
- National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines) colorectal cancer screening version 2.2011. www.nccn.org. Accessed October 2, 2012.
- Jass JR. Hereditary non-polyposis colorectal cancer: the rise and fall of a confusing term. World J Gastroenterol 2006; 12:4943–4950.
- Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM; American College of Gastroenterology. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 2009; 104:739–750.
- Winawer S, Fletcher R, Rex D, et al; Gastrointestinal Consortium Panel. Colorectal cancer screening and surveillance: clinical guidelines and rationale-update based on new evidence. Gastroenterology 2003; 124:544–560.
- Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 2006; 296:1507–1517.
- de Jong AE, Hendriks YM, Kleibeuker JH, et al. Decrease in mortality in Lynch syndrome families because of surveillance. Gastroenterology 2006; 130:665–671.
- Mecklin JP, Aarnio M, Läärä E, et al. Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome. Gastroenterology 2007; 133:1093–1098.
- Engel C, Rahner N, Schulmann K, et al; German HNPCC Consortium. Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 2010; 8:174–182.
- Burn J, Gerdes AM, Macrae F, et al; CAPP2 Investigators. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011; 378:2081–2087.
- Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007; 44:353–362.
- Manchanda R, Menon U, Michaelson-Cohen R, Beller U, Jacobs I. Hereditary non-polyposis colorectal cancer or Lynch syndrome: the gynaecological perspective. Curr Opin Obstet Gynecol 2009; 21:31–38.
- Burn J, Chapman P, Delhanty J, et al. The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations. J Med Genet 1991; 28:289–296.
- Järvinen HJ. Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut 1992; 33:357–360.
- Bisgaard ML, Fenger K, Bülow S, Niebuhr E, Mohr J. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat 1994; 3:121–125.
- Neklason DW, Stevens J, Boucher KM, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin Gastroenterol Hepatol 2008; 6:46–52.
- Burke CA, Beck GJ, Church JM, van Stolk RU. The natural history of untreated duodenal and ampullary adenomas in patients with familial adenomatous polyposis followed in an endoscopic surveillance program. Gastrointest Endosc 1999; 49:358–364.
- Bianchi LK, Burke CA, Bennett AE, Lopez R, Hasson H, Church JM. Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin Gastroenterol Hepatol 2008; 6:180–185.
- Kadmon M, Tandara A, Herfarth C. Duodenal adenomatosis in familial adenomatous polyposis coli. A review of the literature and results from the Heidelberg Polyposis Register. Int J Colorectal Dis 2001; 16:63–75.
- Jarrar AM, Milas M, Mitchell J, et al. Screening for thyroid cancer in patients with familial adenomatous polyposis. Ann Surg 2011; 253:515–521.
- Jasperson KW, Burt RW. APC-associated polyposis conditions. In:Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews (Internet). Seattle, WA: University of Washington; 2011.
- Gardner EJ, Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 1953; 5:139–147.
- Dunlop MG; British Society for Gastroenterology. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut 2002; 51(suppl 5):V21–V27.
- Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997; 277:915–919.
- Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008; 57:704–713.
- Church J. Familial adenomatous polyposis. Surg Oncol Clin N Am 2009; 18:585–598.
- Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993; 328:1313–1316.
- Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342:1946–1952.
- Johnson MD, Mackey R, Brown N, Church J, Burke C, Walsh RM. Outcome based on management for duodenal adenomas: sporadic versus familial disease. J Gastrointest Surg 2010; 14:229–235.
- Phillips RK, Wallace MH, Lynch PM, et al; FAP Study Group. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 2002; 50:857–860.
- Tenesa A, Campbell H, Barnetson R, Porteous M, Dunlop M, Farrington SM. Association of MUTYH and colorectal cancer. Br J Cancer 2006; 95:239–242.
- Croitoru ME, Cleary SP, Di Nicola N, et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 2004; 96:1631–1634.
- Croitoru ME, Cleary SP, Berk T, et al. Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients. J Surg Oncol 2007; 95:499–506.
- Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 2003; 362:39–41.
- Nielsen M, Franken PF, Reinards TH, et al. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet 2005; 42:e54.
- Cleary SP, Cotterchio M, Jenkins MA, et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 2009; 136:1251–1260.
- Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol 2009; 27:3975–3980.
- Aretz S, Uhlhaas S, Goergens H, et al. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 2006; 119:807–814.
- Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 2009; 137:1976–1985.e1–e10.
- Gismondi V, Meta M, Bonelli L, et al. Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int J Cancer 2004; 109:680–684.
- Trepanier A, Ahrens M, McKinnon W, et al; National Society of Genetic Counselors. Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. J Genet Couns 2004; 13:83–114.
- American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 2003; 21:2397–2406.
Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.
Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.
Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:
- Early age of onset of cancer (eg, colorectal cancer before age 50)
- More than 10 colorectal adenomas
- Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
- Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
- A family member with a known hereditary colorectal cancer syndrome (Table 1).
Any of these red flags should prompt a referral for genetic counseling.
SYNDROMES ARE CLASSIFIED AS WITH OR WITHOUT POLYPOSIS
Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).
These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.
In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.
LYNCH SYNDROME (HEREDITARY NONPOLYPOSIS COLORECTAL CANCER)
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.
Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.1 The median age at onset is 45 years.1 For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.2
Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.1
Other extracolonic cancers in Lynch syndrome include cancers of the:
- Stomach (1%–10% risk by age 70 years)
- Ovaries (1%–20% risk)
- Hepatobiliary tract (1%–2% risk)
- Urinary tract (1%–12% risk)
- Small bowel (1%–2% risk)
- Brain (1%–8% risk)
- Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).1,3,4
Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.
Genetics of Lynch syndrome
Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.5 These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.
These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.6
In whom should Lynch syndrome be suspected?
Lynch syndrome can be suspected on the basis of family history and clinical criteria.
In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it1:
- At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
- At least two successive generations involved
- At least one of the cancers diagnosed before age 50
- Familial adenomatous polyposis is excluded.
Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.7 In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).8
Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.
Diagnosis of Lynch syndrome
The diagnosis of Lynch syndrome is based on molecular pathologic analysis (performed on tumor samples) and confirmed by genetic testing.
Molecular pathologic evidence of Lynch syndrome includes microsatellite instability and loss of expression of one or more of the DNA mismatch repair proteins (detected using immunohistochemistry) (more on these below). The revised Bethesda guidelines (TABLE 3) were intended to identify individuals whose tumors should be tested for one or both of these phenomena.9
In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended that all patients with newly diagnosed colorectal cancer undergo microsatellite instability analysis, immunohistochemistry testing, or both, regardless of whether they meet the Amsterdam II or the Bethesda guideline criteria.10
Microsatellite instability analysis. Microsatellites are short sequences of repeated DNA. The tumor cells of patients who carry defective mismatch repair genes have microsatellites that are longer or shorter than in normal cells, a condition called microsatellite instability (ie, “MSI-high”).
Microsatellite instability testing, using a standardized panel of five DNA markers, is performed on normal and tumor tissue. If more than two of the five microsatellite markers in the tumor show instability, the lesion is considered to have a high level of microsatellite instability. About 15% of colorectal cancers have this high level, although most are not associated with Lynch syndrome and lose MLH1 expression by promoter methylation.11,12
While only 2% of patients with colorectal cancer have Lynch syndrome, from 90% to 95% of colorectal cancers from patients with Lynch syndrome have high levels of microsatellite instability.10 The presence of MLH1 promoter hypermethylation, the BRAF mutation V600E, or both within the tumor suggests that the cancer is not associated with Lynch syndrome.
Some families that meet the Amsterdam I criteria have microsatellite-stable tumors: their condition has been called familial colorectal cancer type X.13 This condition is associated with a higher risk of colorectal cancer but not the other malignancies observed in Lynch syndrome.
Immunohistochemistry is performed to assess for expression of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2. Absence of expression of the specific protein within tumor cells compared with normal cells within the specimen suggests dysfunction of the specific gene and guides germline mutation testing (Figure 1). For example, a patient who lacks expression of the MSH2 protein in his or her colon cancer most likely has a mutation in the MSH2 gene. Therefore, germ-line genetic testing should initially target the MSH2 gene. Approximately 88% of Lynch syndrome-associated colorectal cancers have abnormal immunohistochemical staining.10
Testing for microsatellite instability and mismatch repair gene expression ideally precedes germline genetic testing and helps to guide which gene or genes should be tested.9,14
Genetic testing for Lynch syndrome is routinely performed on a blood or saliva sample, using DNA from white blood cells and sequencing the gene or genes involved to look for mutations. Positive results from a germline genetic test confirm the diagnosis of Lynch syndrome and allow for predictive testing for relatives at risk. The term Lynch syndrome is used exclusively to describe individuals with evidence of a mutation in one of the mismatch repair genes.15
If a patient’s results are positive, genetic counseling and genetic testing should be offered to at-risk relatives age 18 and over.
Management of Lynch syndrome
Aggressive cancer surveillance is essential for people with Lynch syndrome and for those who are considered at risk but have not pursued genetic testing, such as a sibling of a person with Lynch syndrome.
Colorectal cancer. Colonoscopy is recommended every 1 to 2 years beginning at the age of 20 to 25 years, or 2 to 5 years earlier than the age of the youngest relative affected with colorectal cancer if the initial diagnosis was before age 25. When patients turn 40 years old, colonoscopy is done annually.16–18 A significant reduction in cancer incidence and in the mortality rate has been shown with colonoscopic surveillance.19–21
Chemoprevention may also have a role. Patients with Lynch syndrome who took aspirin 600 mg per day for an average of 25 months had a significantly lower incidence of colorectal cancer during a 55-month follow-up period compared with patients randomized to placebo.22
For patients with Lynch syndrome who are diagnosed with colorectal cancer, the high risk of metachronous cancers after standard segmental colectomy calls for a more extended resection. Retrospective analysis of 382 Lynch syndrome patients found that none of the 50 who underwent total or subtotal colectomy were diagnosed with metachronous colorectal cancer, whereas a metachronous cancer developed in 74 (22%) of the 332 patients who had had segmented resection.2 Annual surveillance of the remaining colon, rectum, or both is indicated postoperatively.
Gynecologic cancers. Women with Lynch syndrome should also consider gynecologic surveillance and risk-reducing surgery. This includes annual gynecologic examination, transvaginal ultrasonography, and endometrial aspiration, beginning at age 30 to 35 years. Although this surveillance does detect premalignant lesions and early symptomatic cancers, its effect on the mortality rate is unknown. Hysterectomy with bilateral salpingo-oophorectomy has been shown to significantly reduce endometrial and ovarian cancers in women with Lynch syndrome.23,24
Urothelial cancers. Carriers of MSH2 mutations have a significantly higher risk of urothelial cancers.4 Therefore, MSH2 carriers should consider ultrasonography of the urinary tract, urinary cytology, and urinalysis every 1 to 2 years beginning at age 40.4
Other extracolonic cancers. Poor evidence exists for systematic screening for the other extracolonic tumors associated with Lynch syndrome. However, the National Comprehensive Cancer Network advises considering esophagogastroduodenoscopy with extended duodenoscopy as well as capsule endoscopy every 2 to 3 years beginning at age 30 to 35.14
ADENOMATOUS POLYPOSIS SYNDROMES
Familial adenomatous polyposis and MYH-associated polyposis are the next most common hereditary colorectal cancer syndromes. Each of these accounts for about 1% of cases of colorectal cancer. Clinically, these two syndromes can be challenging to distinguish because they overlap phenotypically to a significant degree.
FAMILIAL ADENOMATOUS POLYPOSIS
Familial adenomatous polyposis is caused by mutations in the APC gene. Its prevalence is 2.29 to 3.2 per 100,000 individuals.25,26
Genetics of familial adenomatous polyposis
APC is the only gene known to cause familial adenomatous polyposis. Mutations in APC are inherited in an autosomal dominant manner. Approximately 25% of cases of familial adenomatous polyposis are due to a de novo mutation in APC.27
Clinical presentation of familial adenomatous polyposis
Familial adenomatous polyposis is classified by the burden of colorectal adenomas.
Patients who have fewer than 100 adenomas have an attenuated form of the disease. In this group, polyps usually begin to form in the late teenage years or early 20s and tend to develop in the proximal colon. The attenuated form is associated with an approximately 70% lifetime risk of colorectal cancer.28
Patients who have more than 100 polyps are considered to have the classic form of the disease, and those with more than 1,000 polyps have profuse familial adenomatous polyposis (Figure 2). In these groups, polyps typically begin to develop in the preteenage to mid-teenage years. Without surgery, there is nearly a 100% risk of colorectal cancer. The average age at diagnosis of colorectal cancer is 39 years for patients with classic disease.
Upper gastrointestinal polyps are common in familial adenomatous polyposis. Nearly 90% of patients develop duodenal adenomas by a mean age of 44, with a cumulative lifetime risk of nearly 100%.29 Fundic gland polyposis occurs in nearly 90% of patients,30 while gastric adenomas are reported in fewer than 15% of patients.
Duodenal and periampullary cancer is the second most common malignancy in familial adenomatous polyposis. The lifetime risk ranges from 2% to 36%, depending on the Spigelman stage. People with Spigelman stage I, II, or III have a 2.5% risk of duodenal cancer, while those with stage IV disease have up to a 36% lifetime risk.
Gastric cancer, arising from fundic gland polyps, has been reported but is rare in Western populations.
In familial adenomatous polyposis, the incidence of jejunal adenomas and cancer is less than 10%, and the risk of ileal adenomas and cancer is less than 1%.31
Familial adenomatous polyposis is also associated with a higher risk of other malignancies, including:
- Pancreatic cancer (2% lifetime risk)
- Thyroid cancer (2% to 3% lifetime risk, typically papillary carcinoma)32
- Hepatoblastoma (1% to 2% lifetime risk)
- Brain tumors (< 1% lifetime risk)
- Biliary cancer (higher risk than in the general population).33
Benign extracolonic manifestations that have been observed include osteomas, dental abnormalities (supernumerary teeth, unerupted or absent teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium, benign cutaneous lesions (epidermoid cysts and fibromas), and desmoid tumors.33 The term “Gardner syndrome” has been used to describe patients who have familial adenomatous polyposis but also have osteomas and soft-tissue tumors.34 These patients carry the same risk of colorectal cancer as other patients with familial adenomatous polyposis.
Diagnosing familial adenomatous polyposis
The diagnosis of familial adenomatous polyposis is suspected when a patient has more than 10 adenomatous polyps.
Seventy-five percent of patients with familial adenomatous polyposis have a family history of the condition. Therefore, most cases are identified at a young age on screening sigmoidoscopy or colonoscopy or by predictive gene testing. Patients rarely have cancer at the time of diagnosis.
The other 25% of patients typically are diagnosed when symptoms develop from the polyps or cancer. Over 50% of these symptomatic patients have cancer at the time of diagnosis.
It is recommended that people who have more than 10 adenomas detected on a single colonoscopy or who are first-degree relatives of patients with familial adenomatous polyposis undergo a genetic evaluation and testing for mutations in the APC gene.14 Once an APC mutation is identified in the family, at-risk relatives should be offered testing around age 10 years for families with classic familial adenomatous polyposis or in the mid to late teenage years for those with the attenuated form. It also appropriate to refer patients with desmoid tumors, duodenal adenomas, and bilateral or multifocal congenital hypertrophy of the retinal pigment epithelium for a genetic evaluation.
Management of familial adenomatous polyposis
Flexible sigmoidoscopy every 1 to 2 years beginning at age 10 to 12 years is recommended for individuals and families who have been phenotypically or genetically diagnosed with familial adenomatous polyposis.35–37 If colorectal adenomas are found, surgical options should be discussed and annual colonoscopic surveillance should commence.
For people with the attenuated form, because of the later age of disease onset and the tendency for right-sided disease, colonoscopy every 1 to 2 years should commence at about age 18.35–37 If polyps are found, colonoscopy should be performed every year.
The decision of when to offer colectomy is based on polyp burden (taking into account the number, pathologic appearance, and size of the polyps) and psychosocial factors such as patient maturity. Surgical options include total colectomy and ileorectal anastomosis or total proctocolectomy and ileal pouch anal anastomosis.38 Colonic and extracolonic phenotype as well as genotype should factor into the type of operation recommended. After colectomy, annual endoscopic surveillance of the rectum or ileal pouch is indicated to screen for recurrent polyposis and cancer.
Chemoprevention with sulindac (Clinoril) 150 mg or celecoxib (Celebrex) 400 mg twice a day causes regression of colorectal adenomas in familial adenomatous polyposis and may be useful as an adjunct to endoscopy in managing the colorectal polyp burden.39,40
Forward and side-viewing upper endoscopy should commence at age 20. This should include visualization and biopsy of the papilla and periampulllary region.29 The frequency of endoscopic surveillance depends on the Spigelman stage, which reflects the duodenal polyp burden. It is recommended that patients with Spigelman stage IV duodenal polyposis be seen in consultation with an experienced gastrointestinal surgeon for consideration of a prophylactic, pylorus-preserving, pancreas-sparing duodenectomy. This procedure has been shown to be more effective in polyp control and cancer prevention than endoscopic polyp ablation and local surgical resection.41
Some evidence for the utility of celecoxib 400 mg twice daily for the regression of duodenal polyposis was noted in a 6-month placebo-controlled trial.42 Some experts recommend removal of large duodenal adenomas, with adjunctive celecoxib therapy to control polyposis burden.30
People with familial adenomatous polyposis have been shown to have a 2.6% risk of thyroid cancer, and ultrasonography of the neck with attention to the thyroid is recommended for them.32
MYH-ASSOCIATED POLYPOSIS
Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.
Genetics of MYH-associated polyposis
MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.43 These two mutations are estimated to occur in 1% to 2% of the general population.44
Clinical presentation of MYH-associated polyposis
MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.48 Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.49 Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.49
Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.50,51
Diagnosis of MYH-associated polyposis
Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. 14 It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.52 The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.
Management of MYH-associated polyposis
The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.14 Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.49
GENETIC COUNSELING AND GENETIC TESTING
The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.16 They further recommend genetic counseling and informed consent before genetic testing.16
Genetic counseling is a process of working with patients and families whereby:
- A detailed medical and family history is obtained
- A formal risk assessment is performed
- Education about the disease in question and about genetic testing is provided
- Psychosocial concerns are assessed
- Informed consent is obtained when genetic testing is recommended.53
This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.
In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.54 In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.
When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.
Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.
Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.
Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.
Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.
Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:
- Early age of onset of cancer (eg, colorectal cancer before age 50)
- More than 10 colorectal adenomas
- Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
- Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
- A family member with a known hereditary colorectal cancer syndrome (Table 1).
Any of these red flags should prompt a referral for genetic counseling.
SYNDROMES ARE CLASSIFIED AS WITH OR WITHOUT POLYPOSIS
Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).
These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.
In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.
LYNCH SYNDROME (HEREDITARY NONPOLYPOSIS COLORECTAL CANCER)
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.
Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.1 The median age at onset is 45 years.1 For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.2
Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.1
Other extracolonic cancers in Lynch syndrome include cancers of the:
- Stomach (1%–10% risk by age 70 years)
- Ovaries (1%–20% risk)
- Hepatobiliary tract (1%–2% risk)
- Urinary tract (1%–12% risk)
- Small bowel (1%–2% risk)
- Brain (1%–8% risk)
- Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).1,3,4
Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.
Genetics of Lynch syndrome
Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.5 These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.
These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.6
In whom should Lynch syndrome be suspected?
Lynch syndrome can be suspected on the basis of family history and clinical criteria.
In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it1:
- At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
- At least two successive generations involved
- At least one of the cancers diagnosed before age 50
- Familial adenomatous polyposis is excluded.
Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.7 In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).8
Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.
Diagnosis of Lynch syndrome
The diagnosis of Lynch syndrome is based on molecular pathologic analysis (performed on tumor samples) and confirmed by genetic testing.
Molecular pathologic evidence of Lynch syndrome includes microsatellite instability and loss of expression of one or more of the DNA mismatch repair proteins (detected using immunohistochemistry) (more on these below). The revised Bethesda guidelines (TABLE 3) were intended to identify individuals whose tumors should be tested for one or both of these phenomena.9
In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended that all patients with newly diagnosed colorectal cancer undergo microsatellite instability analysis, immunohistochemistry testing, or both, regardless of whether they meet the Amsterdam II or the Bethesda guideline criteria.10
Microsatellite instability analysis. Microsatellites are short sequences of repeated DNA. The tumor cells of patients who carry defective mismatch repair genes have microsatellites that are longer or shorter than in normal cells, a condition called microsatellite instability (ie, “MSI-high”).
Microsatellite instability testing, using a standardized panel of five DNA markers, is performed on normal and tumor tissue. If more than two of the five microsatellite markers in the tumor show instability, the lesion is considered to have a high level of microsatellite instability. About 15% of colorectal cancers have this high level, although most are not associated with Lynch syndrome and lose MLH1 expression by promoter methylation.11,12
While only 2% of patients with colorectal cancer have Lynch syndrome, from 90% to 95% of colorectal cancers from patients with Lynch syndrome have high levels of microsatellite instability.10 The presence of MLH1 promoter hypermethylation, the BRAF mutation V600E, or both within the tumor suggests that the cancer is not associated with Lynch syndrome.
Some families that meet the Amsterdam I criteria have microsatellite-stable tumors: their condition has been called familial colorectal cancer type X.13 This condition is associated with a higher risk of colorectal cancer but not the other malignancies observed in Lynch syndrome.
Immunohistochemistry is performed to assess for expression of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2. Absence of expression of the specific protein within tumor cells compared with normal cells within the specimen suggests dysfunction of the specific gene and guides germline mutation testing (Figure 1). For example, a patient who lacks expression of the MSH2 protein in his or her colon cancer most likely has a mutation in the MSH2 gene. Therefore, germ-line genetic testing should initially target the MSH2 gene. Approximately 88% of Lynch syndrome-associated colorectal cancers have abnormal immunohistochemical staining.10
Testing for microsatellite instability and mismatch repair gene expression ideally precedes germline genetic testing and helps to guide which gene or genes should be tested.9,14
Genetic testing for Lynch syndrome is routinely performed on a blood or saliva sample, using DNA from white blood cells and sequencing the gene or genes involved to look for mutations. Positive results from a germline genetic test confirm the diagnosis of Lynch syndrome and allow for predictive testing for relatives at risk. The term Lynch syndrome is used exclusively to describe individuals with evidence of a mutation in one of the mismatch repair genes.15
If a patient’s results are positive, genetic counseling and genetic testing should be offered to at-risk relatives age 18 and over.
Management of Lynch syndrome
Aggressive cancer surveillance is essential for people with Lynch syndrome and for those who are considered at risk but have not pursued genetic testing, such as a sibling of a person with Lynch syndrome.
Colorectal cancer. Colonoscopy is recommended every 1 to 2 years beginning at the age of 20 to 25 years, or 2 to 5 years earlier than the age of the youngest relative affected with colorectal cancer if the initial diagnosis was before age 25. When patients turn 40 years old, colonoscopy is done annually.16–18 A significant reduction in cancer incidence and in the mortality rate has been shown with colonoscopic surveillance.19–21
Chemoprevention may also have a role. Patients with Lynch syndrome who took aspirin 600 mg per day for an average of 25 months had a significantly lower incidence of colorectal cancer during a 55-month follow-up period compared with patients randomized to placebo.22
For patients with Lynch syndrome who are diagnosed with colorectal cancer, the high risk of metachronous cancers after standard segmental colectomy calls for a more extended resection. Retrospective analysis of 382 Lynch syndrome patients found that none of the 50 who underwent total or subtotal colectomy were diagnosed with metachronous colorectal cancer, whereas a metachronous cancer developed in 74 (22%) of the 332 patients who had had segmented resection.2 Annual surveillance of the remaining colon, rectum, or both is indicated postoperatively.
Gynecologic cancers. Women with Lynch syndrome should also consider gynecologic surveillance and risk-reducing surgery. This includes annual gynecologic examination, transvaginal ultrasonography, and endometrial aspiration, beginning at age 30 to 35 years. Although this surveillance does detect premalignant lesions and early symptomatic cancers, its effect on the mortality rate is unknown. Hysterectomy with bilateral salpingo-oophorectomy has been shown to significantly reduce endometrial and ovarian cancers in women with Lynch syndrome.23,24
Urothelial cancers. Carriers of MSH2 mutations have a significantly higher risk of urothelial cancers.4 Therefore, MSH2 carriers should consider ultrasonography of the urinary tract, urinary cytology, and urinalysis every 1 to 2 years beginning at age 40.4
Other extracolonic cancers. Poor evidence exists for systematic screening for the other extracolonic tumors associated with Lynch syndrome. However, the National Comprehensive Cancer Network advises considering esophagogastroduodenoscopy with extended duodenoscopy as well as capsule endoscopy every 2 to 3 years beginning at age 30 to 35.14
ADENOMATOUS POLYPOSIS SYNDROMES
Familial adenomatous polyposis and MYH-associated polyposis are the next most common hereditary colorectal cancer syndromes. Each of these accounts for about 1% of cases of colorectal cancer. Clinically, these two syndromes can be challenging to distinguish because they overlap phenotypically to a significant degree.
FAMILIAL ADENOMATOUS POLYPOSIS
Familial adenomatous polyposis is caused by mutations in the APC gene. Its prevalence is 2.29 to 3.2 per 100,000 individuals.25,26
Genetics of familial adenomatous polyposis
APC is the only gene known to cause familial adenomatous polyposis. Mutations in APC are inherited in an autosomal dominant manner. Approximately 25% of cases of familial adenomatous polyposis are due to a de novo mutation in APC.27
Clinical presentation of familial adenomatous polyposis
Familial adenomatous polyposis is classified by the burden of colorectal adenomas.
Patients who have fewer than 100 adenomas have an attenuated form of the disease. In this group, polyps usually begin to form in the late teenage years or early 20s and tend to develop in the proximal colon. The attenuated form is associated with an approximately 70% lifetime risk of colorectal cancer.28
Patients who have more than 100 polyps are considered to have the classic form of the disease, and those with more than 1,000 polyps have profuse familial adenomatous polyposis (Figure 2). In these groups, polyps typically begin to develop in the preteenage to mid-teenage years. Without surgery, there is nearly a 100% risk of colorectal cancer. The average age at diagnosis of colorectal cancer is 39 years for patients with classic disease.
Upper gastrointestinal polyps are common in familial adenomatous polyposis. Nearly 90% of patients develop duodenal adenomas by a mean age of 44, with a cumulative lifetime risk of nearly 100%.29 Fundic gland polyposis occurs in nearly 90% of patients,30 while gastric adenomas are reported in fewer than 15% of patients.
Duodenal and periampullary cancer is the second most common malignancy in familial adenomatous polyposis. The lifetime risk ranges from 2% to 36%, depending on the Spigelman stage. People with Spigelman stage I, II, or III have a 2.5% risk of duodenal cancer, while those with stage IV disease have up to a 36% lifetime risk.
Gastric cancer, arising from fundic gland polyps, has been reported but is rare in Western populations.
In familial adenomatous polyposis, the incidence of jejunal adenomas and cancer is less than 10%, and the risk of ileal adenomas and cancer is less than 1%.31
Familial adenomatous polyposis is also associated with a higher risk of other malignancies, including:
- Pancreatic cancer (2% lifetime risk)
- Thyroid cancer (2% to 3% lifetime risk, typically papillary carcinoma)32
- Hepatoblastoma (1% to 2% lifetime risk)
- Brain tumors (< 1% lifetime risk)
- Biliary cancer (higher risk than in the general population).33
Benign extracolonic manifestations that have been observed include osteomas, dental abnormalities (supernumerary teeth, unerupted or absent teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium, benign cutaneous lesions (epidermoid cysts and fibromas), and desmoid tumors.33 The term “Gardner syndrome” has been used to describe patients who have familial adenomatous polyposis but also have osteomas and soft-tissue tumors.34 These patients carry the same risk of colorectal cancer as other patients with familial adenomatous polyposis.
Diagnosing familial adenomatous polyposis
The diagnosis of familial adenomatous polyposis is suspected when a patient has more than 10 adenomatous polyps.
Seventy-five percent of patients with familial adenomatous polyposis have a family history of the condition. Therefore, most cases are identified at a young age on screening sigmoidoscopy or colonoscopy or by predictive gene testing. Patients rarely have cancer at the time of diagnosis.
The other 25% of patients typically are diagnosed when symptoms develop from the polyps or cancer. Over 50% of these symptomatic patients have cancer at the time of diagnosis.
It is recommended that people who have more than 10 adenomas detected on a single colonoscopy or who are first-degree relatives of patients with familial adenomatous polyposis undergo a genetic evaluation and testing for mutations in the APC gene.14 Once an APC mutation is identified in the family, at-risk relatives should be offered testing around age 10 years for families with classic familial adenomatous polyposis or in the mid to late teenage years for those with the attenuated form. It also appropriate to refer patients with desmoid tumors, duodenal adenomas, and bilateral or multifocal congenital hypertrophy of the retinal pigment epithelium for a genetic evaluation.
Management of familial adenomatous polyposis
Flexible sigmoidoscopy every 1 to 2 years beginning at age 10 to 12 years is recommended for individuals and families who have been phenotypically or genetically diagnosed with familial adenomatous polyposis.35–37 If colorectal adenomas are found, surgical options should be discussed and annual colonoscopic surveillance should commence.
For people with the attenuated form, because of the later age of disease onset and the tendency for right-sided disease, colonoscopy every 1 to 2 years should commence at about age 18.35–37 If polyps are found, colonoscopy should be performed every year.
The decision of when to offer colectomy is based on polyp burden (taking into account the number, pathologic appearance, and size of the polyps) and psychosocial factors such as patient maturity. Surgical options include total colectomy and ileorectal anastomosis or total proctocolectomy and ileal pouch anal anastomosis.38 Colonic and extracolonic phenotype as well as genotype should factor into the type of operation recommended. After colectomy, annual endoscopic surveillance of the rectum or ileal pouch is indicated to screen for recurrent polyposis and cancer.
Chemoprevention with sulindac (Clinoril) 150 mg or celecoxib (Celebrex) 400 mg twice a day causes regression of colorectal adenomas in familial adenomatous polyposis and may be useful as an adjunct to endoscopy in managing the colorectal polyp burden.39,40
Forward and side-viewing upper endoscopy should commence at age 20. This should include visualization and biopsy of the papilla and periampulllary region.29 The frequency of endoscopic surveillance depends on the Spigelman stage, which reflects the duodenal polyp burden. It is recommended that patients with Spigelman stage IV duodenal polyposis be seen in consultation with an experienced gastrointestinal surgeon for consideration of a prophylactic, pylorus-preserving, pancreas-sparing duodenectomy. This procedure has been shown to be more effective in polyp control and cancer prevention than endoscopic polyp ablation and local surgical resection.41
Some evidence for the utility of celecoxib 400 mg twice daily for the regression of duodenal polyposis was noted in a 6-month placebo-controlled trial.42 Some experts recommend removal of large duodenal adenomas, with adjunctive celecoxib therapy to control polyposis burden.30
People with familial adenomatous polyposis have been shown to have a 2.6% risk of thyroid cancer, and ultrasonography of the neck with attention to the thyroid is recommended for them.32
MYH-ASSOCIATED POLYPOSIS
Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.
Genetics of MYH-associated polyposis
MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.43 These two mutations are estimated to occur in 1% to 2% of the general population.44
Clinical presentation of MYH-associated polyposis
MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.48 Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.49 Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.49
Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.50,51
Diagnosis of MYH-associated polyposis
Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. 14 It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.52 The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.
Management of MYH-associated polyposis
The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.14 Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.49
GENETIC COUNSELING AND GENETIC TESTING
The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.16 They further recommend genetic counseling and informed consent before genetic testing.16
Genetic counseling is a process of working with patients and families whereby:
- A detailed medical and family history is obtained
- A formal risk assessment is performed
- Education about the disease in question and about genetic testing is provided
- Psychosocial concerns are assessed
- Informed consent is obtained when genetic testing is recommended.53
This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.
In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.54 In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.
When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.
Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.
Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.
- Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011; 305:2304–2310.
- Parry S, Win AK, Parry B, et al. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 2011; 60:950–957.
- Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 2009; 75:141–149.
- van der Post RS, Kiemeney LA, Ligtenberg MJ, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet 2010; 47:464–470.
- Wijnen JT, Vasen HF, Khan PM, et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998; 339:511–518.
- Bisgaard ML, Bernstein I. HNPCC mutation rate. Familial Cancer 2003; 2.
- Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991; 34:424–425.
- Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999; 116:1453–1456.
- Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004; 96:261–268.
- Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Genet Med 2009; 11:15–20.
- Aaltonen LA, Peltomäki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993; 260:812–816.
- Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994; 145:148–156.
- Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293:1979–1985.
- National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines) colorectal cancer screening version 2.2011. www.nccn.org. Accessed October 2, 2012.
- Jass JR. Hereditary non-polyposis colorectal cancer: the rise and fall of a confusing term. World J Gastroenterol 2006; 12:4943–4950.
- Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM; American College of Gastroenterology. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 2009; 104:739–750.
- Winawer S, Fletcher R, Rex D, et al; Gastrointestinal Consortium Panel. Colorectal cancer screening and surveillance: clinical guidelines and rationale-update based on new evidence. Gastroenterology 2003; 124:544–560.
- Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 2006; 296:1507–1517.
- de Jong AE, Hendriks YM, Kleibeuker JH, et al. Decrease in mortality in Lynch syndrome families because of surveillance. Gastroenterology 2006; 130:665–671.
- Mecklin JP, Aarnio M, Läärä E, et al. Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome. Gastroenterology 2007; 133:1093–1098.
- Engel C, Rahner N, Schulmann K, et al; German HNPCC Consortium. Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 2010; 8:174–182.
- Burn J, Gerdes AM, Macrae F, et al; CAPP2 Investigators. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011; 378:2081–2087.
- Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007; 44:353–362.
- Manchanda R, Menon U, Michaelson-Cohen R, Beller U, Jacobs I. Hereditary non-polyposis colorectal cancer or Lynch syndrome: the gynaecological perspective. Curr Opin Obstet Gynecol 2009; 21:31–38.
- Burn J, Chapman P, Delhanty J, et al. The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations. J Med Genet 1991; 28:289–296.
- Järvinen HJ. Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut 1992; 33:357–360.
- Bisgaard ML, Fenger K, Bülow S, Niebuhr E, Mohr J. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat 1994; 3:121–125.
- Neklason DW, Stevens J, Boucher KM, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin Gastroenterol Hepatol 2008; 6:46–52.
- Burke CA, Beck GJ, Church JM, van Stolk RU. The natural history of untreated duodenal and ampullary adenomas in patients with familial adenomatous polyposis followed in an endoscopic surveillance program. Gastrointest Endosc 1999; 49:358–364.
- Bianchi LK, Burke CA, Bennett AE, Lopez R, Hasson H, Church JM. Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin Gastroenterol Hepatol 2008; 6:180–185.
- Kadmon M, Tandara A, Herfarth C. Duodenal adenomatosis in familial adenomatous polyposis coli. A review of the literature and results from the Heidelberg Polyposis Register. Int J Colorectal Dis 2001; 16:63–75.
- Jarrar AM, Milas M, Mitchell J, et al. Screening for thyroid cancer in patients with familial adenomatous polyposis. Ann Surg 2011; 253:515–521.
- Jasperson KW, Burt RW. APC-associated polyposis conditions. In:Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews (Internet). Seattle, WA: University of Washington; 2011.
- Gardner EJ, Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 1953; 5:139–147.
- Dunlop MG; British Society for Gastroenterology. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut 2002; 51(suppl 5):V21–V27.
- Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997; 277:915–919.
- Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008; 57:704–713.
- Church J. Familial adenomatous polyposis. Surg Oncol Clin N Am 2009; 18:585–598.
- Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993; 328:1313–1316.
- Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342:1946–1952.
- Johnson MD, Mackey R, Brown N, Church J, Burke C, Walsh RM. Outcome based on management for duodenal adenomas: sporadic versus familial disease. J Gastrointest Surg 2010; 14:229–235.
- Phillips RK, Wallace MH, Lynch PM, et al; FAP Study Group. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 2002; 50:857–860.
- Tenesa A, Campbell H, Barnetson R, Porteous M, Dunlop M, Farrington SM. Association of MUTYH and colorectal cancer. Br J Cancer 2006; 95:239–242.
- Croitoru ME, Cleary SP, Di Nicola N, et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 2004; 96:1631–1634.
- Croitoru ME, Cleary SP, Berk T, et al. Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients. J Surg Oncol 2007; 95:499–506.
- Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 2003; 362:39–41.
- Nielsen M, Franken PF, Reinards TH, et al. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet 2005; 42:e54.
- Cleary SP, Cotterchio M, Jenkins MA, et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 2009; 136:1251–1260.
- Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol 2009; 27:3975–3980.
- Aretz S, Uhlhaas S, Goergens H, et al. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 2006; 119:807–814.
- Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 2009; 137:1976–1985.e1–e10.
- Gismondi V, Meta M, Bonelli L, et al. Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int J Cancer 2004; 109:680–684.
- Trepanier A, Ahrens M, McKinnon W, et al; National Society of Genetic Counselors. Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. J Genet Couns 2004; 13:83–114.
- American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 2003; 21:2397–2406.
- Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011; 305:2304–2310.
- Parry S, Win AK, Parry B, et al. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 2011; 60:950–957.
- Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 2009; 75:141–149.
- van der Post RS, Kiemeney LA, Ligtenberg MJ, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet 2010; 47:464–470.
- Wijnen JT, Vasen HF, Khan PM, et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998; 339:511–518.
- Bisgaard ML, Bernstein I. HNPCC mutation rate. Familial Cancer 2003; 2.
- Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991; 34:424–425.
- Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999; 116:1453–1456.
- Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004; 96:261–268.
- Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Genet Med 2009; 11:15–20.
- Aaltonen LA, Peltomäki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993; 260:812–816.
- Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994; 145:148–156.
- Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293:1979–1985.
- National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines) colorectal cancer screening version 2.2011. www.nccn.org. Accessed October 2, 2012.
- Jass JR. Hereditary non-polyposis colorectal cancer: the rise and fall of a confusing term. World J Gastroenterol 2006; 12:4943–4950.
- Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM; American College of Gastroenterology. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 2009; 104:739–750.
- Winawer S, Fletcher R, Rex D, et al; Gastrointestinal Consortium Panel. Colorectal cancer screening and surveillance: clinical guidelines and rationale-update based on new evidence. Gastroenterology 2003; 124:544–560.
- Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 2006; 296:1507–1517.
- de Jong AE, Hendriks YM, Kleibeuker JH, et al. Decrease in mortality in Lynch syndrome families because of surveillance. Gastroenterology 2006; 130:665–671.
- Mecklin JP, Aarnio M, Läärä E, et al. Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome. Gastroenterology 2007; 133:1093–1098.
- Engel C, Rahner N, Schulmann K, et al; German HNPCC Consortium. Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 2010; 8:174–182.
- Burn J, Gerdes AM, Macrae F, et al; CAPP2 Investigators. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011; 378:2081–2087.
- Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007; 44:353–362.
- Manchanda R, Menon U, Michaelson-Cohen R, Beller U, Jacobs I. Hereditary non-polyposis colorectal cancer or Lynch syndrome: the gynaecological perspective. Curr Opin Obstet Gynecol 2009; 21:31–38.
- Burn J, Chapman P, Delhanty J, et al. The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations. J Med Genet 1991; 28:289–296.
- Järvinen HJ. Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut 1992; 33:357–360.
- Bisgaard ML, Fenger K, Bülow S, Niebuhr E, Mohr J. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat 1994; 3:121–125.
- Neklason DW, Stevens J, Boucher KM, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin Gastroenterol Hepatol 2008; 6:46–52.
- Burke CA, Beck GJ, Church JM, van Stolk RU. The natural history of untreated duodenal and ampullary adenomas in patients with familial adenomatous polyposis followed in an endoscopic surveillance program. Gastrointest Endosc 1999; 49:358–364.
- Bianchi LK, Burke CA, Bennett AE, Lopez R, Hasson H, Church JM. Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin Gastroenterol Hepatol 2008; 6:180–185.
- Kadmon M, Tandara A, Herfarth C. Duodenal adenomatosis in familial adenomatous polyposis coli. A review of the literature and results from the Heidelberg Polyposis Register. Int J Colorectal Dis 2001; 16:63–75.
- Jarrar AM, Milas M, Mitchell J, et al. Screening for thyroid cancer in patients with familial adenomatous polyposis. Ann Surg 2011; 253:515–521.
- Jasperson KW, Burt RW. APC-associated polyposis conditions. In:Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews (Internet). Seattle, WA: University of Washington; 2011.
- Gardner EJ, Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 1953; 5:139–147.
- Dunlop MG; British Society for Gastroenterology. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut 2002; 51(suppl 5):V21–V27.
- Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997; 277:915–919.
- Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008; 57:704–713.
- Church J. Familial adenomatous polyposis. Surg Oncol Clin N Am 2009; 18:585–598.
- Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993; 328:1313–1316.
- Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342:1946–1952.
- Johnson MD, Mackey R, Brown N, Church J, Burke C, Walsh RM. Outcome based on management for duodenal adenomas: sporadic versus familial disease. J Gastrointest Surg 2010; 14:229–235.
- Phillips RK, Wallace MH, Lynch PM, et al; FAP Study Group. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 2002; 50:857–860.
- Tenesa A, Campbell H, Barnetson R, Porteous M, Dunlop M, Farrington SM. Association of MUTYH and colorectal cancer. Br J Cancer 2006; 95:239–242.
- Croitoru ME, Cleary SP, Di Nicola N, et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 2004; 96:1631–1634.
- Croitoru ME, Cleary SP, Berk T, et al. Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients. J Surg Oncol 2007; 95:499–506.
- Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 2003; 362:39–41.
- Nielsen M, Franken PF, Reinards TH, et al. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet 2005; 42:e54.
- Cleary SP, Cotterchio M, Jenkins MA, et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 2009; 136:1251–1260.
- Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol 2009; 27:3975–3980.
- Aretz S, Uhlhaas S, Goergens H, et al. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 2006; 119:807–814.
- Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 2009; 137:1976–1985.e1–e10.
- Gismondi V, Meta M, Bonelli L, et al. Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int J Cancer 2004; 109:680–684.
- Trepanier A, Ahrens M, McKinnon W, et al; National Society of Genetic Counselors. Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. J Genet Couns 2004; 13:83–114.
- American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 2003; 21:2397–2406.
KEY POINTS
- Hereditary colorectal cancer syndromes carry a substantial risk of intestinal and extraintestinal tumors.
- Affected patients need increased cancer surveillance and may benefit from prophylactic surgery.
- Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history.
- Patients suspected of having hereditary colorectal cancer syndromes should be referred for genetic counseling and, if appropriate, for genetic testing.
