Major Genes
Adenomatous Polyposis Coli (APC)
Mut Y Homolog
DNA Mismatch Repair Genes
Peutz-Jeghers Gene(s)
Juvenile Polyposis Gene
Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome Gene(s)

Major Genes

Major genes are defined as those that are necessary and sufficient for disease causation, with important mutations (e.g., nonsense, frameshift) of the gene as causal mechanisms. Major genes are typically considered those that are involved in single-gene disorders, and the diseases caused by major genes are often relatively rare. Most pathogenic mutations in major genes lead to a very high risk of disease, and environmental contributions are often difficult to recognize.[1] Historically, most major colon cancer susceptibility genes have been identified by linkage analysis using high-risk families; thus, these criteria were fulfilled by definition, as a consequence of the study design.

The functions of the major colon cancer genes have been reasonably well characterized over the past decade. Three proposed classes of colon cancer genes are tumor suppressor genes, oncogenes, and stability genes.[2] Tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for both familial adenomatous polyposis (FAP) and juvenile polyposis, among others. Germline mutations of oncogenes are not an important cause of inherited susceptibility to colorectal cancer, even though somatic mutations in oncogenes are ubiquitous in virtually all forms of gastrointestinal cancers. Stability genes, especially the mismatch repair genes responsible for Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]), account for a substantial fraction of hereditary colorectal cancer, as noted below (see section on Lynch syndrome). MYH is another important example of a stability gene that confers risk of colorectal cancer on the basis of defective base excision repair. Table 2 summarizes the genes that confer a substantial risk of colorectal cancer, with their corresponding diseases.

Several reviews have been published describing the hereditary colon cancer genes.[3-5]

The APC gene on chromosome 5q21 encodes a 2,843-amino acid protein that is important in cell adhesion and signal transduction; beta-catenin is its major downstream target. APC is a tumor suppressor gene, and the loss of APC is among the earliest events in the chromosomal instability (CIN) colorectal tumor pathway. The important role of APC in predisposition to colorectal tumors is supported by the association of APC germline mutations with FAP and attenuated FAP (AFAP). Both conditions can be diagnosed genetically by testing for germline mutations in the APC gene in DNA from peripheral blood leukocytes. Most FAP pedigrees have APC alterations that produce truncating mutations, primarily in the first half of the gene.[6,7] AFAP is associated with truncating mutations primarily in the 5’ and 3’ ends of the gene and possibly missense mutations elsewhere.[8-11]

More than 300 different disease-associated mutations of the APC gene have been reported.[7] The vast majority of these changes are insertions, deletions, and nonsense mutations that lead to frameshifts and/or premature stop codons in the resulting transcript of the gene. The most common APC mutation (10% of FAP patients) is a deletion of AAAAG in codon 1309; no other mutations appear to predominate. Mutations that reduce rather than eliminate production of the APC protein may also lead to FAP.[12]

Most APC mutations that occur between codon 169 and codon 1393 result in the classic FAP phenotype.[8-10] There has been much interest in correlating the location of the mutation within the gene with the clinical phenotype, including the distribution of extracolonic tumors, polyposis severity, and congenital hypertrophy of the retinal pigment epithelium. The most consistent observations are that attenuated polyposis and the less classic forms of FAP are associated with mutations that occur in the latter two-thirds of exon 15,[9] and that retinal lesions are rarely associated with mutations that occur before exon 9.[10,13]

The Mut Y homolog (MYH) gene, located on chromosome 1p, has been implicated in individuals with multiple adenomas and colorectal cancer. MYH is one of several base excision-repair genes that corrects oxidative DNA damage. Failure to correct this damage can lead to the formation of 8-oxoG, causing an increase in G:C→T:A transversions. MYH was suspected as a susceptibility gene after researchers examined somatic mutations in the APC gene from a kindred without a germline APC mutation consisting of two siblings with multiple (about 50) adenomas and one sibling with colorectal cancer and adenomas. Somatic G:C→T:A transversions were identified in the APC gene in adenomas and colorectal cancer from these siblings, suggesting the possibility of underlying germline mutations in the MYH gene.[14] Thus, the APC protein is a major downstream target of MYH mutations.[15] Notably, the occurrence of multiple adenomas was primarily found in patients with mutations in both alleles (i.e., biallelic mutations), suggesting an autosomal recessive mode of inheritance. A study of 152 patients with multiple adenomas and 107 patients with APC mutation-negative polyposis found two major germline mutations, Y165C and G382D, in addition to other variants.[16] Understanding the significance of these additional variants will require further research in comprehensive analysis of the MYH gene in larger study populations.

Lynch syndrome is caused by mutation of one of several DNA mismatch repair genes.[17-23] The function of these genes is to maintain the fidelity of DNA during replication. The genes that have been implicated in Lynch syndrome include hMSH2 (human mutS homolog 2) on chromosome 2p16;[20,21] hMLH1 (human mutL homolog 1) on chromosome 3p21;[19] PMS2 (postmeiotic segregation 2) on chromosome 7p22;[23,24] and hMSH6 on chromosome 2p16. The genes hMSH2 and hMLH1 are thought to account for most mutations of the mismatch repair genes found in Lynch syndrome families.[25,26]

A variety of Lynch syndrome-associated mutations in hMSH2 and hMLH1 have been identified and catalogued, including founder mutations in the Ashkenazi Jewish (hMSH2 1906G-->C), Finnish (hMLH1 Fin 1 mutation), and German American (hMSH2 exons 1–6 deletion) populations.[26-29] The wide distribution of the mutations in the two genes preclude simple gene testing assays (i.e., assays that would identify only a few mutations). Commercial testing is available to search for mutations in hMSH2 and hMLH1. Clinical and cost considerations may guide testing strategies. Most commercial genetic testing for hMSH2 and hMLH1 is done by gene sequencing. Because sequencing fails to detect genomic deletions that are relatively common in Lynch syndrome, methods such as Southern blot or multiplex ligation-dependent probe amplification (MLPA),[30] for detection of large deletions, are being used.[31] Issues to be considered in testing for these mutations are reviewed in the Genetic/Molecular testing for Lynch syndrome section of this summary.

Germline mutation analysis for hMSH2, hMLH1, hMSH6, and/or PMS2 may be recommended for suspected Lynch syndrome patients after screening the tumors for microsatellite instability (MSI) and/or the absence of protein expression. Microsatellites are short, repetitive sequences of mononucleotides, dinucleotides, and trinucleotides located throughout the genome, primarily in intronic sequences.[32] Tumor DNA that shows alterations in microsatellite regions indicates probable defects in mismatch repair genes, which may be due to somatic or germline mutations in mismatch repair genes.[33] Similarly, absence of hMSH2, hMLH1, and hMSH6 protein expression has been shown to have a high predictive value to detect germline mutations. However, loss of protein expression may not be seen in all MSI-high (MSI-H) tumors.[34,35]

At a molecular level, the mismatch repair genes encode proteins that are responsible for correcting mispairing of DNA nucleotide bases and the small insertions or deletions that frequently occur during normal DNA replication. Thus, the mismatch repair system maintains the fidelity of genomic DNA.[36,37] While haploinsufficient cells have normal or nearly normal repair activity, cells in which both alleles of the mismatch repair gene are nonfunctional lack the ability to repair DNA replication mismatches. Evidence for this hypermutable state within the cell is seen by the insertion or deletion of mononucleotide, dinucleotide, or trinucleotide base pair repeats in the microsatellite tracts in the genomic DNA taken from tumor cells.[38] When these repetitive elements are replicated incorrectly and not repaired by the mismatch repair proteins, MSI ensues. The resulting genomic instability is thought to be responsible for the rapid accumulation of somatic mutations in oncogenes and tumor suppressor genes in the cell’s genome that have crucial roles in the initiation and progression of tumors.[39]

Because many colon cancers demonstrate frameshift mutations at a small percentage of microsatellite repeats, the designation of an adenocarcinoma as showing MSI depends, in part, on the detection of a specified percentage of unstable loci from a panel of dinucleotide and mononucleotide repeats that were selected at a National Institutes of Health Consensus conference.[38] If a tumor shows more than 30% to 40% of markers are unstable, it is scored as MSI-H; if fewer than 30% to 40% of markers are unstable, the tumor is designated MSI-low. If no loci are unstable, the tumor is designated microsatellite stable (MSS). Most tumors arising in the setting of Lynch syndrome will be MSI-H.[38] One important distinction is that people with germline mutations in hMSH6 do not necessarily manifest the MSI-H phenotype.

The role of MSI analysis has led to the development of the Revised Bethesda Guidelines, which set forth clinical indications for use of this assay (including Lynch syndrome) and standardization of tumor analysis.[38,40,41] Even simpler assays to screen tumors are being evaluated. One method that has been reported is immunohistochemistry, using monoclonal antibodies to the hMLH1 and hMSH2 proteins. Loss of expression of either protein appears to correlate with the presence of MSI and may suggest which specific mismatch repair gene is altered in a particular patient.[34,42-44]

Peutz-Jeghers syndrome (PJS) is characterized by mucocutaneous pigmentation and gastrointestinal polyposis and is caused by mutations in the STK11 (also named LKB1) tumor suppressor gene located on chromosome 19p13.[45,46] Unlike the adenomas seen in FAP, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (loss of heterozygosity [LOH]) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene.[47,48] However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency is sufficient for initial tumor development in PJS.[49] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[50] indeed, compound mutant mice heterozygous for mutations in STK11 +/- and homozygous for mutations in TP53 -/- have accelerated development of both hamartomas and cancers.[51]

Germline mutations of the STK11 gene represent a spectrum of nonsense, frameshift, and missense mutations, as well as splice-site variants.[52] Large deletions appear to be uncommon.[53] Approximately 85% of mutations are localized to regions of the kinase domain of the expressed protein, and no germline mutations have been reported in exon 9. No strong genotype-phenotype correlations have been identified.[52]

Only one gene (STK11) has been unequivocally demonstrated to cause PJS, but there is some evidence of locus heterogeneity that suggests the involvement of at least one other gene.[54,55] Mutations in STK11 can be identified in approximately 70% of patients,[53] and some families without identifiable mutations show linkage to 19q13.4. In addition, a novel chromosomal translocation involving 19q13.4 was identified in a PJS polyp from a 6-day-old infant, providing further evidence of the existence of a second PJS gene in this region. Recent data suggest that the combination of direct sequencing and MLPA enable detection of STK11 mutations in up to 94% of patients meeting clinical criteria for PJS.[56] Given the results of this study, it is unlikely that other major genes cause PJS.

(Refer to the Peutz-Jeghers syndrome section in the PDQ summary on the Genetics of Breast and Ovarian Cancer for more information.)

Juvenile polyposis is defined by the presence of a specific type of hamartomatous polyp called a juvenile polyp, usually in the setting of a family history. The diagnosis of a juvenile polyp is based on its histologic appearance rather than age of onset, and the familial form is caused by mutations in the BMPR1A gene in 20% of cases and by mutations in the SMAD4 gene in another 20%.[57,58]

SMAD4 encodes a protein that is a mediator of the TGF-beta signaling pathway, which mediates growth inhibitory signals from the cell surface to the nucleus. Germline mutations in SMAD4 predispose individuals to forming juvenile polyps and cancer,[59] and germline mutations have been found in 6 of 11 exons. Most mutations are unique, but several recurrent mutations have been identified in multiple independent families.

BMPR1A is a serine-threonine kinase type I receptor of the TGF-beta superfamily that, when activated, leads to phosphorylation of SMAD4. The BMPR1A gene was first identified by linkage analysis in families with juvenile polyposis who did not have identifiable mutations in SMAD4. Mutations in BMPR1A include nonsense, frameshift, missense, and splice-site mutations.[60] Large genomic deletions detected by MLPA have been reported in both BMPR1A and SMAD4 in patients with juvenile polyposis syndrome. It was also reported that two individuals had mutations in both PTEN and BMPR1A.[61] Rare juvenile polyposis syndrome families have demonstrated mutations in the ENG and PTEN genes but these have not been confirmed in other studies.[61,62]

Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes (PHTS). Approximately 85% of patients diagnosed with Cowden syndrome and approximately 60% of patients with BRRS have an identifiable mutation of PTEN.[63]

PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine as well as serine and threonine. Mutations of PTEN are diverse, including nonsense, missense, frameshift, and splice-variant mutations. Approximately 40% of mutations are found in exon 5, which represents the phosphate core motif, and several recurrent mutations have been observed.[64] Individuals with mutations in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.[65]

(Refer to the Cowden Syndrome section in the PDQ summary on the Genetics of Breast and Ovarian Cancer for more information.)

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