Genetics of Colorectal Cancer

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

The Genetic Paradigm of Colorectal Cancer Formation

In 1990, Fearon and Vogelstein^[2] presented evidence for a multistep genetic model for the formation of CRC. This model is based on the understanding that CRC is the result of mutations in key genes, including the inactivation of TSGs and the activation of oncogenes. Moreover, accumulation of mutations occurs in a sequential manner, with mutations of some genes preceding that of others. This genetic paradigm is shown in Figure 2. As seen, there are 2 different pathways that lead to the formation of CRC. One route is through inactivation of the TSG, adenomatous polyposis coli (APC), which accounts for approximately 85% of all CRC and is mutated in the germline of patients with FAP. The other pathway for development of CRC is through the mutational inactivation of a family of proteins involved in DNA mismatch repair (MMR), including MSH2, MLH1, and PMS2. MMR mutation is found in approximately 15% of all sporadic CRC and is responsible for the HNPCC syndrome.

(Enlarge Image)

The genetic paradigm of colorectal cancer. The formation of CRC requires the sequential mutation of several genes. This includes the inactivation of TSGs (in green) and activation of oncogenes (in red). There are 2 independent pathways that can cause CRC, depending upon which TSG is first inactivated. Inactivation of the APC gene is found in about 85% of sporadic CRC, and inactivation of the mismatch repair genes, including MSH2, MLH1, and PMS2, is found in the remaining 15%.Key: COX-2 = cyclo-oxygenase-2.

Mutations in the MMR genes cause genetic defects in other genes that are involved in growth control and behave like TSGs. The APC pathway of CRC formation often includes activation of oncogenes such as COX-2 and K-RAS and inactivation of additional TSGs such as DCC/DPC4 and p53 (Figure 2).

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Cite this: Genetics of Colorectal Cancer - Medscape - Aug 13, 2004.

Abstract and Introduction
Classification of Cancer-Causing Genes
The Genetic Paradigm of Colorectal Cancer Formation
Hereditary Polyposis Syndromes
Genetic Testing
Conclusion
References

Clinical Criteria for the Diagnosis of HNPCC
The Amsterdam Criteria (1991)
Three or more relatives with colorectal cancer, plus all of the following: One affected patient should be a first-degree relative of the other 2; Colorectal cancer should involve at least 2 generations; and At least 1 case of colorectal cancer diagnosed before the age of 50 years.
Amsterdam II Criteria (1998)
Three or more relatives with HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis) plus all of the following: One affected patient should be a first-degree relative of the other 2; Two or more successive generations should be affected; Cancer in 1 or more affected relatives should be diagnosed before the age of 50 years; Familial adenomatous polyposis should be excluded in any cases of colorectal cancer; and Tumors should be verified by pathologic examination.
The Bethesda Guidelines (1997)
Just 1 of these criteria needs to be met: Individuals with cancer in families that fulfill the Amsterdam criteria; Individuals with 2 HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers (which include endometrial, ovarian, gastric, hepatobiliary or small-bowel cancer, or transitional-cell carcinoma of the renal pelvis or ureter); Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal adenoma; one of the cancers must have been diagnosed before the age of 45 years and the adenoma diagnosed before the age of 40 years; Individuals with colorectal cancer or endometrial cancer that was diagnosed before the age of 45 years; Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribiform) on histopathology, which was diagnosed before the age of 45 years; Individuals with signet-ring-cell-type colorectal cancer that was diagnosed by the age of 45 years; or Individuals with adenomas that were diagnosed by the age of 40 years.

Clinical Criteria for the Diagnosis of HNPCC
The Amsterdam Criteria (1991)
Three or more relatives with colorectal cancer, plus all of the following: One affected patient should be a first-degree relative of the other 2; Colorectal cancer should involve at least 2 generations; and At least 1 case of colorectal cancer diagnosed before the age of 50 years.
Amsterdam II Criteria (1998)
Three or more relatives with HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis) plus all of the following: One affected patient should be a first-degree relative of the other 2; Two or more successive generations should be affected; Cancer in 1 or more affected relatives should be diagnosed before the age of 50 years; Familial adenomatous polyposis should be excluded in any cases of colorectal cancer; and Tumors should be verified by pathologic examination.
The Bethesda Guidelines (1997)
Just 1 of these criteria needs to be met: Individuals with cancer in families that fulfill the Amsterdam criteria; Individuals with 2 HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers (which include endometrial, ovarian, gastric, hepatobiliary or small-bowel cancer, or transitional-cell carcinoma of the renal pelvis or ureter); Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal adenoma; one of the cancers must have been diagnosed before the age of 45 years and the adenoma diagnosed before the age of 40 years; Individuals with colorectal cancer or endometrial cancer that was diagnosed before the age of 45 years; Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribiform) on histopathology, which was diagnosed before the age of 45 years; Individuals with signet-ring-cell-type colorectal cancer that was diagnosed by the age of 45 years; or Individuals with adenomas that were diagnosed by the age of 40 years.

Clinical Criteria for the Diagnosis of HNPCC
The Amsterdam Criteria (1991)
Three or more relatives with colorectal cancer, plus all of the following: One affected patient should be a first-degree relative of the other 2; Colorectal cancer should involve at least 2 generations; and At least 1 case of colorectal cancer diagnosed before the age of 50 years.
Amsterdam II Criteria (1998)
Three or more relatives with HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis) plus all of the following: One affected patient should be a first-degree relative of the other 2; Two or more successive generations should be affected; Cancer in 1 or more affected relatives should be diagnosed before the age of 50 years; Familial adenomatous polyposis should be excluded in any cases of colorectal cancer; and Tumors should be verified by pathologic examination.
The Bethesda Guidelines (1997)
Just 1 of these criteria needs to be met: Individuals with cancer in families that fulfill the Amsterdam criteria; Individuals with 2 HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers (which include endometrial, ovarian, gastric, hepatobiliary or small-bowel cancer, or transitional-cell carcinoma of the renal pelvis or ureter); Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal adenoma; one of the cancers must have been diagnosed before the age of 45 years and the adenoma diagnosed before the age of 40 years; Individuals with colorectal cancer or endometrial cancer that was diagnosed before the age of 45 years; Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribiform) on histopathology, which was diagnosed before the age of 45 years; Individuals with signet-ring-cell-type colorectal cancer that was diagnosed by the age of 45 years; or Individuals with adenomas that were diagnosed by the age of 40 years.

Clinical Criteria for the Diagnosis of HNPCC
The Amsterdam Criteria (1991)
Three or more relatives with colorectal cancer, plus all of the following: One affected patient should be a first-degree relative of the other 2; Colorectal cancer should involve at least 2 generations; and At least 1 case of colorectal cancer diagnosed before the age of 50 years.
Amsterdam II Criteria (1998)
Three or more relatives with HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis) plus all of the following: One affected patient should be a first-degree relative of the other 2; Two or more successive generations should be affected; Cancer in 1 or more affected relatives should be diagnosed before the age of 50 years; Familial adenomatous polyposis should be excluded in any cases of colorectal cancer; and Tumors should be verified by pathologic examination.
The Bethesda Guidelines (1997)
Just 1 of these criteria needs to be met: Individuals with cancer in families that fulfill the Amsterdam criteria; Individuals with 2 HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers (which include endometrial, ovarian, gastric, hepatobiliary or small-bowel cancer, or transitional-cell carcinoma of the renal pelvis or ureter); Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal adenoma; one of the cancers must have been diagnosed before the age of 45 years and the adenoma diagnosed before the age of 40 years; Individuals with colorectal cancer or endometrial cancer that was diagnosed before the age of 45 years; Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribiform) on histopathology, which was diagnosed before the age of 45 years; Individuals with signet-ring-cell-type colorectal cancer that was diagnosed by the age of 45 years; or Individuals with adenomas that were diagnosed by the age of 40 years.

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