Genetics of Colorectal Cancer

Irfan M. Hisamuddin, MD; Vincent W. Yang, MD, PhD

In This Article

Hereditary Polyposis Syndromes

FAP is an autosomal dominant disorder in which patients typically develop CRC in early adult life, secondary to extensive adenomatous polyp formation in the colon. Polyps also develop in the upper gastrointestinal tract, and malignancies may occur in other sites, including the brain and the thyroid. A phenotypic variant of FAP -- the Gardner syndrome -- is characterized by colonic polyposis with extraintestinal tumors, especially osteomas, and a rather characteristic retinal lesion known as congenital hypertrophy of the retinal pigment. The onset of polyposis in affected individuals often coincides with puberty, and untreated patients invariably develop CRC, with a median age at diagnosis of 40 years. Prophylactic colectomy is the treatment of choice once colonic polyposis is manifested.

The first clue to the location of the gene for FAP was provided in a study by Herrera and colleagues,[3] which demonstrated a constitutional deletion of chromosome 5q21 in a patient with Gardner syndrome. Subsequent linkage analysis demonstrated that 5q21 chromosome markers were linked to the development of FAP.[4,5] The gene responsible for FAP was identified in 1991 and was termed the APC gene.[6,7,8] Studies also demonstrated the presence of point mutations in the APC gene in the germline of patients with FAP.[7,9] In adenomas and carcinomas that develop in FAP patients, there is evidence for the inactivation of the second copy of the APC gene.[9,10,11] These findings strongly support Knudson's "2-hit" hypothesis for tumorigenesis[12] and indicate that APC is a TSG in CRC.

The APC gene contains 15 exons and a single open reading frame of 8538 nucleotides that encodes a protein of 2843 amino acids.[8] Mutations in the APC gene are present in 80% to 85% of patients with FAP[13] and in over 80% of cases of sporadic CRC.[14] It has been shown that a process termed loss of heterozygosity (LOH) is the main mechanism by which APC becomes inactivated. In this process, the first allele of the APC gene contains an inactivating point mutation in the germline or somatic DNA of patients with FAP or sporadic CRC, respectively. Approximately 90% of the point mutations in APC in CRC cause an inactive, truncated protein product. Most of these mutations accumulate in the central region of the APC gene, which is known as the mutation cluster region, and result in expression of carboxyl-terminally truncated proteins. APC mutations in the first or last third of the gene are associated with an attenuated polyposis with a late onset and a small number of polyps,[15] whereas mutations in the central region of the gene correlate with a severe phenotype characterized by thousands of polyps at a young age and with additional extracolonic manifestations. Nonneoplastic cells of patients with FAP are expected to retain normal APC function due to the presence of 1 wild-type allele, irrespective of the position of the mutation in the affected allele. Consistent with the Knudson 2-hit model, the wild-type APC allele is lost in a great majority of colorectal tumors in both sporadic and FAP disease.[14]

HNPCC is the most common form of inherited CRC to date. This syndrome is an autosomal dominant disease, with a population incidence of approximately 1:1000, and is responsible for up to 5% of all cases of CRC (Figure 2). Patients with HNPCC have up to an 80% lifetime risk of developing CRC, and a 60% lifetime risk of developing endometrial carcinoma. Affected individuals are also at an increased risk for other cancers, such as stomach, ovarian, small bowel, biliary, and kidney cancers. In contrast to FAP, patients with HNPCC develop adenomas at a normal rate but progress more rapidly through the stages of carcinogenesis.[16] Relative to sporadic CRC, adenomas and carcinomas in HNPCC occur predominantly in the proximal colon due to an increased rate of transformation.[17] Diagnosis of HNPCC is primarily based on clinical criteria, some of which are outlined in Table 1 . The Amsterdam Criteria were the first diagnostic guidelines to be developed, but they can only identify approximately 60% of the patients with HNPCC.[18] The latter led to the development of the revised criteria (Amsterdam II Criteria; Table 1 ), which take into consideration the presence of extracolonic cancer and have a sensitivity of detection of approximately 80%. New guidelines (The Bethesda Guidelines; Table 1 ) were also developed to aid in the decision process regarding whether patients who do not fulfill Amsterdam Criteria should undergo gene testing for HNPCC, and this further increased the sensitivity of detection to 94%.[18]

The pathogenesis of HNPCC is typified by the presence of widespread alterations in short, repeated DNA sequences in tumor cells -- a phenomenon called microsatellite instability (MSI).[13] This phenomenon indicates that numerous replication errors occur during the formation of tumors. Indeed, subsequent genetic analysis identified the culprits in HNPCC as a group of TSGs that encode proteins involved in repairing mismatched DNA sequences (MMR genes; Figure 2). The genes identified to date include MSH2, MLH1, PMS2, MSH6, and PMS1.[19] Among these, approximately 85% of the mutations involve MSH2 and MLH1. An important consequence of mutations in the MMR genes is the subsequent inactivation of other genes due to the presence of microsatellite sequences in their coding regions. Some of these targeted genes are involved in important aspects of regulation of cell proliferation. Examples include the type II receptor for transforming growth factor beta;[20,21] the type II receptor for the insulin-like growth factor 2;[22] and BAX, which is involved in the control of apoptosis.[23,24] Inactivation of these genes leads to derangement of cell proliferation and subsequent tumor formation.

Hamartoma refers to an excessive but focal overgrowth of cells and tissues native to the organ in which it occurs. Although the cellular elements are mature and identical to those found in the remainder of the organ, they do not reproduce the normal architecture of the surrounding tissue. In the intestinal tract, several discrete familial syndromes characterized by multiple hamartomatous polyps have been described -- these include the Peutz-Jeghers syndrome, juvenile polyposis syndrome, and related syndromes such as Cowden's syndrome and Bannayan-Ruvalcaba-Riley syndrome. The hamartomatous polyps in these diseases are derived from the epithelial, stromal, or from both components, of the intestine. Affected patients are at risk for developing cancer of the intestinal tract.

Peutz-Jeghers Syndrome. This syndrome is an autosomal dominant disorder first described by Peutz in 1921, followed by Jeghers in 1949. Characteristics of this disease include the presence of pigmentation on the lips, buccal mucosa, hands, and feet; hamartomatous polyps throughout the gastrointestinal tract; and increased risk for gastrointestinal, breast, ovarian, and testicular cancers. The cumulative risk of colon cancer is 39%, with similar rates for gastric and pancreatic cancer.[25] Peutz-Jeghers syndrome is caused by germline mutations in STK11/LKB1, a serine-threonine kinase gene on chromosome 19p.[26,27] However, not all families with this syndrome are linked to defects in this gene locus, suggesting there is heterogeneity. Recent evidence for loss of STK11/LKB1 expression in Peutz-Jeghers polyps, even without dysplastic epithelium, raises the possibility that the STK11/LKB1 gene itself may be the gatekeeper to carcinogenesis in this syndrome, much as the APC gene is the gatekeeper in FAP.[28]

Juvenile Polyposis Syndrome. Juvenile polyps are distinctive hamartomas that have a smooth surface and are covered by normal colonic epithelium. Juvenile polyposis syndrome is defined by any 1 of the following criteria: 10 or more colonic juvenile polyps; juvenile polyps throughout the gastrointestinal tract; or any number of juvenile polyps, with a family history of juvenile polyposis. The risk of colon cancer is increased in familial juvenile polyposis, with cancer occurring at an average age of 34 years. Although the juvenile polyps per se are not considered neoplastic, the synchronous adenomatous polyps and mixed juvenile-adenomatous polyps of these patients may give rise to concern.

Most families with this syndrome have germline mutations of the DPC4/SMAD4 gene, a TSG that plays a role in signaling through the transforming growth factor-beta cascade.[29] Some families with juvenile polyposis syndrome carry mutations in the PTEN gene, a tumor suppressor with phosphatase activity.[30] It should be noted, however, that PTEN mutations have also been described in Cowden's syndrome and in Bannayan-Ruvalcaba-Riley syndrome.[31,32] Therefore, classifying a patient with a PTEN mutation can be problematic because, depending upon the syndrome (juvenile polyposis syndrome, Cowden's syndrome, and Bannayan-Ruvalcaba-Riley syndrome), the risks for various cancers and, hence, appropriate management, differ.

APC I1307K Mutation

Most of the APC mutations found in hereditary and sporadic CRC are nonsense mutations (ie, they lead to the formation of a truncated protein). In contrast, the APC I1307K mutation is a missense point mutation in nucleotide position 3920, causing a T to A transversion and, consequently, the substitution of lysine (K) for isoleucine (I) in amino acid position 1307 of the APC protein.[33] This mutation is predominantly seen in Ashkenazi Jews and carries a predisposition to CRC.[34] The increased risk for CRC is about 2-fold, indicating that the mutation has a low penetrance despite a relatively high prevalence of about 6.1% in American Jews of European origin.[33] This polymorphism suggests a paradigm wherein subtle mutations in the APC gene, as compared with distinct well-characterized APC mutations found in FAP, may contribute to hereditary CRC.

-Associated Polyposis

Although the majority of FAP is attributed to germline mutations in the APC gene, a small number of familial cases of polyposis have no identified APC mutations. Recent studies of these APC-negative probands identified germline mutations in the MYH gene, which functions in base excision repair. Somatic mutations in the APC gene can be found in tumors from carriers with biallelic mutations that are either missense or nonsense.[35] Hereditary polyposis due to MYH mutations has been termed MYH-associated polyposis and follows a distinct genetic pathway.[36] It has been estimated that MYH-associated polyposis contributes to approximately 1% of unselected CRC.[37]


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