Genetics of Colorectal Cancer

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

Genetic Testing

The approach to genetic testing in individuals and family members at risk for CRC requires a well thought-out rationale, with a systematic identification of the proband, the at-risk family, appropriate pretest genetic counseling, laboratory investigations, and, finally, posttest counseling and clinical follow-up. If a mutation is detected in a proband, family members should be offered testing. If a family member tests negative, then he should be reassured as to the lack of need for further screening but be reminded of the fact that he still has the background population risk.

Genetic testing for FAP is performed using a commercially available in vitro synthesized protein assay to detect truncated APC protein.^[13] The sensitivity of this test is approximately 65%, with false-negative results seen in about 20% of patients. Therefore, the disease is ruled out for an individual only if there is no mutation found in an affected family member.^[38] Genetic testing for HNPCC is more complex because any 1 of a host of genes may be mutated, although defects in MLH1 and MSH2 are responsible for the disease in about 85% of cases. Furthermore, only 50% of patients who meet the Amsterdam criteria will have positive results on MLH1 and MSH2 testing, raising concerns about false negatives. Additional guidelines have been devised in an attempt to increase the yield for identification of HNPCC ( Table 1 ).^[39] Many of the newly published guidelines include examination of the tumors for MSI and level of MMR expression by immunohistochemistry.^[40]

The issue of genetic testing has significant ethical connotations. The anxiety associated with testing, the implications of false-negative results, the financial aspects of testing, vis a vis insurance coverage, and the privacy issues associated with genetic testing should all be carefully and judiciously addressed. The process of testing should involve thorough genetic counseling of the patient and family members, both before and after the test. Testing should be offered after close consultation with the patient and family and in those cases where a reasonable correlation and benefit is evident.

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

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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Genetics of Colorectal Cancer

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