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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Colon Cancer Genes

Major Genes

Major genes are defined as those that are necessary and sufficient for disease causation, with important mutations (e.g., nonsense, missense, 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 DNA repair 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 (CRC), even though somatic mutations in oncogenes are ubiquitous in virtually all forms of gastrointestinal cancers. Stability genes, especially the mismatch repair (MMR) genes responsible for Lynch syndrome (LS) (also called hereditary nonpolyposis colorectal cancer [HNPCC]), account for a substantial fraction of hereditary CRC, as noted below. (Refer to the Lynch syndrome (LS) section in the Major Genetic Syndromes section of this summary for more information). MYH is another important example of a stability gene that confers risk of CRC based on defective base excision repair. Table 2 summarizes the genes that confer a substantial risk of CRC, with their corresponding diseases.

Table 2. Major Genes Associated with Risk of Colorectal Cancer

GeneSyndromeHereditary PatternPredominant Cancer
FAP = familial adenomatous polyposis; GI = gastrointestinal; OMIM = Online Mendelian Inheritance in Man database.
Adapted from Vogelstein et al.[2]
Tumor suppressor genes   
APC(OMIM)FAP (OMIM)DominantColon, intestine, etc.
AXIN2(OMIM)Attenuated polyposis (OMIM)DominantColon
TP53(p53) (OMIM)Li-Fraumeni (OMIM)DominantMultiple (including colon)
STK11(OMIM)Peutz-Jeghers (OMIM)DominantMultiple (including intestine)
PTEN(OMIM)Cowden (OMIM)DominantMultiple (including intestine)
BMPR1A(OMIM)Juvenile polyposis (OMIM)DominantGastrointestinal
SMAD4(DPC4) (OMIM)Juvenile polyposis (OMIM)DominantGastrointestinal
Repair/stability genes   
MLH1(OMIM),MSH2(OMIM),MSH6(OMIM),PMS2 (OMIM)Lynch (OMIM)DominantMultiple (including colon, uterus, and others)
EPCAM (TACSTD1) (OMIM)Lynch (OMIM)DominantMultiple (including colon, uterus, and others)
MYH(MUTYH) (OMIM)Attenuated polyposis (OMIM)RecessiveColon
BLM(OMIM)Bloom (OMIM)RecessiveMultiple (including colon)
Oncogenes   
KIT(OMIM)Familial GI stromal tumor (OMIM) GI stromal tumors
PDGFRA(OMIM)Familial GI stromal tumor (OMIM) GI stromal tumors

Several reviews have been published describing the hereditary colon cancer genes.[3,4,5]

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