Hereditary Colorectal Cancer Syndromes Associated With Mutations in Known Genes
Lynch syndrome is the most common of the hereditary CRC syndromes and has been implicated in 2% to 4% of CRC cases. It is characterized by a predisposition to develop colorectal, endometrial, and selected other cancers, which often arise at young ages. Affected families frequently include multiple relatives with cancer and display an autosomal-dominant pattern of inheritance. Estimated lifetime risks for developing cancer range from 22% to 75% for CRC and 32% to 45% for endometrial cancer, with risks for other cancers (including ovarian, gastric, small intestinal, urinary tract, brain, pancreatic, and sebaceous neoplasms of the skin) also increased. Although the Amsterdam Criteria (3 cases of CRC, involving 2 generations with 1 case diagnosed at age younger than 50 years) originally were used for identifying affected families, the discovery of germline mutations in the DNA mismatch repair (MMR) genes hMLH1, hMSH2, hMSH6, and hPMS2 elucidated the genetic basis of the disease. More than 90% of Lynch-associated CRC tumors show phenotypes of high DNA microsatellite instability (MSI-H) and loss of expression of MMR proteins MLH1, MSH2, MSH6, or PMS2 by immunohistochemistry. Although these tumors tend to develop at younger ages and feature accelerated neoplastic progression, early initiation of colonoscopy with frequent surveillance intervals is effective in reducing CRC incidence and mortality and has altered the natural history of the disease for many affected families. Consensus recommendations for CRC screening include intensive surveillance with colonoscopy every 1 to 2 years starting at age 20 to 25 years. Although evidence supporting the effectiveness of screening for extracolonic cancers is limited, upper gastrointestinal endoscopy at 3–5 year intervals starting at age 30 to 35 years, and annual endometrial biopsy and transvaginal ultrasound for women starting at age 30 to 35 years may be considered (Table 1).
The distinctive MMR-deficient tumor phenotype, high cancer risk, and effectiveness of surveillance make Lynch syndrome an attractive target for population-based screening among individuals diagnosed with CRC. Systematic screening of tumors for MMR deficiency, using MSI and/or immunohistochemistry, has emerged as a sensitive means to identify individuals who develop CRC as a result of heritable MMR mutations. Models suggest that the strategy of screening all CRC cases for features of Lynch syndrome is cost effective, mainly as a result of benefits derived from implementation of early interventions that prevent cancers in at-risk family members. The use of risk-assessment models that rely on personal and family cancer history to estimate an individual's probability of carrying a MMR gene mutation (eg, PREMM1,2,6 and MMRPro) also has been proposed as a cost-effective means for screening all individuals for Lynch syndrome, regardless of cancer status.
Familial Adenomatous Polyposis
Familial adenomatous polyposis (FAP) is the second most common of the inherited CRC syndromes after Lynch syndrome and accounts for approximately 1% of newly diagnosed CRC cases. In cases of classic polyposis, the phenotype of hundreds to thousands of adenomatous polyps in the colon makes FAP easily recognizable. In most cases, affected individuals develop colorectal adenomas by the second or third decade of life. The lifetime risk for CRC is estimated to exceed 90% for individuals who do not undergo surgical colectomy. More than half of individuals with FAP develop adenomas in the upper gastrointestinal tract and cancers of the duodenum/ampulla are the second leading cause of cancer death for FAP patients, after CRC. Risks for other cancers, including papillary thyroid cancer, adrenal carcinomas, and central nervous system tumors, also are increased. Intra-abdominal desmoid tumors appear in some individuals with FAP and can be associated with significant morbidity and mortality.
In 90% of classic FAP cases, germline mutations in the adenomatous polyposis coli (APC) gene can be detected through clinical genetic testing. APC is a tumor-suppressor gene involved in the WNT signaling pathway and somatic loss of function of APC is one of the first steps in the colorectal adenoma-carcinoma sequence. Individuals with germline mutations in APC develop multiple adenomas at very young ages as a result of inactivation of the remaining allele in colonic epithelial cells. Although FAP is associated with autosomal-dominant inheritance, approximately 30% of affected individuals report no family history of the disease. Although most of these represent de novo APC mutations, biallelic mutations in MutYH, a DNA base excision repair gene involved in the repair of oxidative damage, also have been identified in some patients with classic polyposis. Unlike FAP, MutYH-associated polyposis is associated with an autosomal-recessive pattern of inheritance. Biallelic MutYH mutation carriers can show a wide range of phenotypes; although some individuals have colonic and extracolonic manifestations indistinguishable from classic FAP, most cases are associated with attenuated phenotypes showing fewer than 100 adenomas. The Y179C and G396D mutations are the 2 most common pathogenic alterations in MutYH in individuals of western European ancestry but other mutations are reported among individuals of other races and ethnicities. Population-based studies have identified monoallelic and biallelic MutYH mutations in 0.7% and 1.7% of unselected CRC cases, respectively. Biallelic gene mutation carriers have a 28-fold increased risk of developing CRC compared with the general population, whereas the risk in monoallelic carriers is increased by less than 2-fold.
Although clinical genetic testing for individuals affected with adenomatous polyposis has been available since the early 1990s, the sensitivity of testing has improved over time. Full sequencing of the APC gene, in conjunction with multiplex ligation-dependent probe amplification, detects mutations in 90% of individuals with classic polyposis. In the absence of an identifiable APC mutation, testing for the Y165C and G382D mutations in MutYH is indicated, with full gene sequencing of MutYH recommended for individuals who are found to have 1 of these 2 mutations or whose racial/ethnic ancestry is not western European. However, approximately 1 in 10 individuals with the classic FAP phenotype do not have identifiable mutations in APC or MutYH. Although there are reports of somatic mosaicism for APC mutations, this likely explains only a small fraction of cases. Efforts to identify other genes implicated in cases of classic FAP without APC or MutYH mutations are underway.
Identification of mutations in APC or MutYH in families with adenomatous polyposis has significant implications for at-risk family members. If a mutation is identified in an affected individual, predictive genetic testing of other family members provides an opportunity to identify those who require intensive surveillance. Individuals who are confirmed carriers of APC mutations should begin annual colorectal surveillance at age 10 to 12 years, whereas individuals who test negative for the known mutation in the family can undergo screening according to population-based guidelines. Although the severity of polyposis phenotypes among carriers of MutYH mutations can be variable, it generally is recommended that biallelic carriers undergo surveillance similar to APC mutation carriers, whereas monoallelic carriers can wait to begin surveillance according to moderate-risk guidelines for CRC.
Hamartomatous Polyposis Syndromes
Hamartomatous polyposis, defined as more than 3 to 5 hamartomatous polyps in the gastrointestinal tract, is implicated in less than 0.5% of all CRC cases. Although rare, the hamartomatous polyposis syndromes can be associated with increased risks for a variety of extraintestinal cancers and the diagnosis has significant implications for medical management. Consequently, the finding of one or more gastrointestinal hamartomas in the setting of a suspicious family history of cancer is considered an indication for genetic evaluation.
Peutz–Jeghers syndrome (PJS) is characterized by multiple intestinal hamartomatous polyps, mucocutaneous pigmentation, and a high lifetime risk of gastrointestinal, pancreatic, and breast cancers. PJS is quite rare with an incidence estimated at 1 in 150,000. The clinical diagnosis requires 2 or more of the following features: (1) mucocutaneous pigmentation (eg, freckling in mouth/lips, fingers); (2) 2 or more Peutz–Jeghers type gastrointestinal hamartomas; or (3) family history of PJS. Individuals with PJS can develop hamartomatous polyps throughout their gastrointestinal tract and often present with symptoms of abdominal pain, gastrointestinal bleeding with anemia, intestinal obstruction, or intussusception. The lifetime risk for developing any cancer by age 70 has been estimated at 85% to 90%, with gastrointestinal cancers (colon, small intestine, stomach, pancreas) and breast seen most commonly. Mutations in the serine threonine kinase 11 (STK-11 also known as LKB-1) tumor-suppressor gene involved in the mammalian target of rapamycin pathway have been found in approximately 50% to 70% of PJS patients. Although genetic testing can be helpful in confirming the diagnosis, it is not informative in many individuals with a clinical diagnosis of PJS. To date, no genes other than STK-11 have been associated with PJS. Patients with PJS and their at-risk relatives require frequent endoscopic surveillance for removal of polyps throughout the gastrointestinal tract, as well as screening for extraintestinal cancers (Table 1). Although techniques such as computed tomography/magnetic resonance enterography and capsule endoscopy have facilitated detection of small-bowel polyps in patients with PJS, the evidence to support the use of one imaging modality over the others is limited.
Juvenile polyposis syndrome (JPS) is characterized by multiple (≥3–5) juvenile polyps and increased risk for gastrointestinal cancers. Affected individuals often present in childhood with symptoms of anemia, bleeding, or abdominal pain. Juvenile polyps are found most often in the stomach or colon and less often in the small bowel. Certain congenital abnormalities, including cardiac valvular disease and/or atrial and ventricular septal defects, can be seen in some affected families. Individuals with JPS are at increased risk for gastric cancer and CRC, with a lifetime risk approaching 40% to 50%.
Mutations in the SMAD4 and BMPR1A genes are found in approximately 50% of individuals with a clinical diagnosis of JPS. These genes encode proteins involved in the transforming growth factor (TGF)-β signaling pathway. More recently, mutations in ENG, also involved in the TGF-β pathway, have been found in a small number of patients with JPS. Although clinical genetic testing can be useful for risk-stratifying relatives when a gene mutation is identified in the family, for many patients who meet the clinical criteria for JPS, genetic testing is clinically uninformative. Individuals with a personal or family history of juvenile polyposis should begin upper and lower endoscopy starting at age 15, with a goal of removal of all large polyps.
Cowden syndrome, also known as Bannayan Riley Ruvalcaba syndrome and phosphatase and tensin homolog (PTEN)–hamartoma tumor syndrome, has been associated with a broad range of clinical phenotypes. It is caused by mutations in the PTEN gene, which confers increased risk for cancers, most commonly breast, thyroid, and endometrial. Although Cowden syndrome often is included among the colorectal hamartoma syndromes, there is significant variability in the colonic polyp phenotype. A retrospective review of findings of gastrointestinal endoscopy examinations in 64 individuals with PTEN mutations reported heterogeneity in polyp number and histologic types (hamartomas, adenomas, serrated polyps, hyperplastic polyps, and ganglioneuromas); however, the finding that 13% had been diagnosed with CRC at younger than age 50 suggests that early colonoscopic screening may be justified in these individuals.