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Genetics of Colorectal Cancer

Genetics of Colorectal Cancer

Approximately 6% of colorectal cancers can be attributed to recognizable heritable germline mutations. Familial adenomatous polyposis is an autosomal dominant syndrome classically presenting with hundreds to thousands of adenomatous colorectal polyps that are caused by mutations in the APC gene. Adenomas typically develop in the midteens in these patients, and colorectal cancer is a virtual certainty if this condition is untreated. A low-penetrance susceptibility allele that is common in Jews from Eastern Europe, APC I1307K, confers a twofold increased risk of colorectal cancer without the full expression of familial adenomatous polyposis. Biallelic mutations in the MYH gene are associated with an attenuated familial adenomatous polyposis phenotype. Lynch syndrome (hereditary nonpolyposis colorectal cancer) is an autosomal dominant disorder characterized by early onset of colorectal cancer with microsatellite instability. Mutations in mismatch repair genes lead to a lifetime colon cancer risk of 85% in these patients; carcinomas of the endometrium, ovary, and other organs also occur with increased frequency. Although adenomas are not characteristic of the hamartomatous polyp syndromes such as juvenile polyposis and Peutz-Jeghers syndrome, individuals with these diseases have a markedly increased risk of colorectal cancer relative to the general population. In this review, we will describe the phenotypes, genotypes, diagnosis, and management of hereditary colon cancer syndromes.

In the United States, 6% of individuals will develop colorectal cancer in their lifetime. The vast majority of colorectal cancers (approximately 65% to 85%) are con-sidered sporadic, as they are not attributable to identified cancer syndromes or a family history of colorectal cancer. An additional 10% to 30% of cancers are termed familial, indicating that colorectal cancer is present in a first- or second-degree relative, but no specific germline mutation has been identified as responsible for increased susceptibility. Identifiable germline mutations cause approximately 6% of all colorectal cancers.[1] The purpose of this review is to outline the characteristics, diagnosis, and management of hereditary colorectal cancer syndromes caused by germline mutations, including familial -adenomatous polyposis, Lynch syndrome (hereditary nonpolyposis colorectal cancer), juvenile polyposis, and Peutz-Jeghers syndromes.

Familial Adenomatous Polyposis

Although familial adenomatous polyposis (FAP) accounts for only about 0.5% to 1% of colon cancers, its clinical presentation can be quite distinctive, consisting of hundreds to thousands of polyps in the colon and upper gastrointestinal tract. Individ­uals with this syndrome, if left untreated, have a virtual certainty of developing colon cancer within their lifetime. The mean age for development of colon adenomas is 16 years for classic FAP, and the mean age for diagnosis of colon cancer in untreated individuals is 36.[2] An attenuated form of FAP, also known as the hereditary flat adenoma syndrome, consists of fewer than 100 colon polyps, rather than the hundreds or more found in the classic form of FAP. Some clinical presentations of attenuated FAP are characterized by relative sparing of the rectum and a tendency for right-sided colon lesions. The age at colon cancer diagnosis in attenuated FAP is between that of classic FAP and that of the general population; it averages 10 to 20 years later than in classic FAP, or around age 50 to 60.[3]

Other Associated Findings

Fundic gland polyps of the stomach and adenomas of the duodenum are other characteristic gastrointestinal lesions that are often found in this disorder. Approximately 50% of individuals with FAP have gastric fundus polyps, and 10% have adenomas of the stomach. Although gastric fundus polyps are unlikely to have malignant potential, gastric adenomas can occasionally develop into invasive disease.[4] Adenomas of the small bowel can be found in 50% to 90% of patients with FAP and most commonly occur in the distal portions of the duodenum. A substantial proportion of FAP patients may have adenomas of the ampulla of Vater or the duodenal papillae, which may cause pancreatitis and have a higher risk of malignant transformation than other polyps found in the duodenum.[5]

Benign tumors outside of the gastrointestinal tract that are associated with FAP include osteomas, desmoid tumors, adrenal adenomas, and cutaneous fibromas. Although the majority of these lesions do not cause significant morbidity or mortality, desmoid tumors have the potential to become locally invasive and can be extremely difficult to manage. Desmoid tumors develop in approximately 10% of FAP patients and are associated with pregnancy, oral contraceptive use, and abdominal surgery. Half of the patients with these tumors experience significant related morbidity and mortality. The combination of colonic adenomatous polyposis, desmoid tumors, fibromas, and osteomas has been described as Gardner syndrome, although FAP remains the more commonly used term.[6] Other physical examination findings that occur more frequently in FAP patients include supernumerary teeth, unerupted or absent teeth, odontomas, epidermoid cysts, and congenital hypertrophy of the retinal pigment epithelium (CHRPE)-a pigmented lesion of the retina that does not affect the vision. Unilateral CHRPE lesions can be found in the general population, but bilateral or multiple CHRPE lesions suggest a diagnosis of FAP.[7]

Individuals with FAP also have an increased incidence of certain extracolonic tumors relative to the general population. Cancers of the duodenum or ampulla occur in 4% to 12% of patients with FAP and are a leading cause of morbidity and mortality among FAP patients who have been treated with a total colectomy. Stomach cancers may develop in 0.5% of FAP patients and usually arise from gastric adenomas rather than fundic gland polyps. Approximately 2% of FAP patients develop pancreatic cancer.[8] Thyroid cancer may develop in approximately 2% of FAP patients, with a mean age of 28 at diagnosis. The majority of these cancers are papillary thyroid carcinomas.

Pediatric patients under age 5 have an increased incidence of hepatoblastoma, with an absolute risk of 1.6%. Turcot syndrome consists of colon cancer associated with increased risk of cancers of the central nervous system; two-thirds of these patients have FAP.[9] The tumor type most often seen in this syndrome in conjunction with FAP is medulloblastoma, which is present in less than 1% of all FAP patients. Finally, the risks of biliary and adrenal cancers, although still quite low, are increased in the FAP population relative to the general -population.[10]

Genetic Testing

Most cases of classic and attenuated FAP can be attributed to mutations to the APC gene, a tumor-suppressor gene located on chromosome 5q21-q22.[11,12] Deleterious mutations in this gene cause premature truncation of the APC protein. Up to 25% of individuals with FAP will have a de novo mutation. Studies of genotype-phenotype correlations have shown that attenuated FAP is associated with mutations at the 5´ and 3´ ends of the gene, as well as in exon 9.[13-15] Desmoids and osteomas occur more frequently in patients with mutations of codons 1400 to 1580, and congenital hypertrophy of the retinal pigment epithelium is associated with mutations in codons 457 to 1444.[16]

Genetic testing of the APC gene that combines sequencing of the coding regions and analysis for large deletions and rearrangements will detect mutations in 90% to 95% of families with a clinical diagnosis of FAP. Once a mutation has been identified in an affected family member, other family members can be tested for the specific alteration with essentially 100% accuracy. Cost-effectiveness analysis has shown that genetic testing to identify individuals with FAP is superior to performing regular endoscopy for all individuals potentially at risk.[17] It has also been demonstrated that life expectancy is greater for individuals who are diagnosed with FAP prior to the onset of symptoms. Finally, appropriate surgical management of these patients can be determined by the results of genetic testing. As more is learned about genotype/phenotype correlations, knowledge of the specific familial mutation may play a greater role in management decisions.


Patients with classic FAP require close endoscopic surveillance starting at an early age. Screening guidelines vary, but most suggest that sigmoidoscopy or colonoscopy should be initiated between the ages of 10 and 12 and performed every 1 to 2 years until polyps are too numerous to be managed endoscopically; at that time, colectomy should be considered. After colectomy, endoscopy of the rectal remnant or ileal pouch is needed on an annual basis. Esophagogastroduodenoscopy (EGD) with use of a side-viewing scope to visualize the duodenum should begin at age 25 or at the time of detection of polyps in the lower gastrointestinal tract. A staging system for severity of duodenal adenomas has been developed by Spigelman in order to determine appropriate management.[18] Depending on Spigelman stage, EGD should be repeated every 1 to 3 years. If the duodenum is severely affected, consideration of surgery is appropriate. Small-bowel imaging by enteroclysis or capsule endoscopy may be considered when severe duodenal polyposis is detected.

Individuals from families with attenuated FAP should start colonoscopy between the ages of 18 and 20 years, and colonoscopy should be done every 2 to 3 years. However, one needs to be cautious with these recommendations as it can be difficult to distinguish attenuated FAP from classic FAP in small families. There is no consensus as to whether colectomy is mandatory in these patients once polyps are identified; some elect to reserve colectomy only in patients whose polyps cannot be managed endoscopically. Similarly, upper endoscopy is recommended by most authors because of the marked phenotypic variation in this syndrome.

Screening for tumors outside of the gastrointestinal tract includes regular monitoring of the liver by ultrasound and alpha-fetoprotein levels to rule out hepatoblastoma from infancy to age 5, although consensus has not been reached for this recommendation. Annual physical examination of the thyroid is also recommended. At present, screening measures are not available for desmoid tumors and other tumors associated with FAP.


Chemoprevention, particularly with nonsteroidal anti-inflammatory drugs (NSAIDs), has been an area of active investigation in families with FAP. Several studies of sulindac and COX-2 inhibitors have demonstrated temporary regression of adenomas in this population. Celecoxib (Celebrex) received accelerated Food and Drug Administration approval based on data showing a reduction of polyp burden in individuals with FAP, although the clinical benefit of this drug was not established. These modestly encouraging results must be balanced with the recent data showing that rofecoxib (Vioxx, a COX-2 inhibitor that was taken off the market) increases the risk of cardiovascular events.

Although COX-2 inhibitors are unlikely to play a role in colon cancer prevention in the general population, additional studies with longer follow-up may demonstrate a favorable risk-benefit ratio for these medications as chemoprevention in the FAP population. In the setting of FAP, COX-2 inhibitors currently are useful for individuals with a low polyp burden in the rectal remnant to delay the timing of complete proctectomy.


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