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1、American Gastroenterological Association medical position statement: Hereditary colorectal cancer and genetic testingThis document presents the official recommendations of the American Gastroenterological Association (AGA) on Hereditary Colorectal Cancer and Genetic Testing. It was approved by the C
2、linical Practice and Practice Economics Committee on March 20, 2001, and the AGA Governing Board on April 18, 2001. GASTROENTEROLOGY 2001;121:195-197The following guidelines were developed to assist the primary care physician, internist, surgeon, and gastroenterologist with the appropriate provision
3、 of genetic testing for hereditary colorectal cancer. Hereditary colorectal cancer refers to familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), the 2 best described hereditary syndromes for which genetic testing is clinically available.The integration of gene
4、tic testing into clinical practice provides multiple benefits to individuals in families with histories of colorectal cancer. These benefits include earlier detection of colorectal neoplasm and prevention of cancer, removal of patient uncertainty, greater choice of surgical and other intervention op
5、tions, elimination of unnecessary screening, and provision of information for planning family and career decisions. In hereditary colorectal cancer, genetic testing has been shown to be cost-effective. Finally, past experience of health care providers in offering genetic testing has shown a need for
6、 greater education and guidelines.Genetic testing recommendationsFAP Indications FAP is caused by mutation of the adenomatous polyposis coli (APC) gene. Genetic testing for APC gene mutation should be used to screen for FAP. APC gene testing is indicated to confirm the diagnosis of FAP, provide pres
7、ymptomatic testing for at-risk members (first degree relatives 10 years or older of an affected patient), confirm the diagnosis of attenuated FAP in those with 20 adenomas, and test those 10 years or older at risk for attenuated FAP (Figure 1). . Fig. 1. FAP gene testing.Appropriate strategy Genetic
8、 testing of both affected and at-risk individuals requires pretest genetic counseling and written informed consent. Germline testing should first be performed on an affected member of the family to establish a detectable mutation in the pedigree, usually by protein truncation testing. If a mutation
9、is found in an affected family member, then genetic testing of at-risk members will provide true positive or negative results. Appropriate screening strategies can then be undertaken based on the at-risk persons gene test result. If a pedigree mutation is not identified, further testing of at-risk r
10、elatives should be suspended because the gene test will not be conclusive: a negative result could be a false negative because the protein truncation testing is not capable of detecting a mutation even if present. When an affected family member is not available for evaluation, starting the test proc
11、ess with at-risk family members can provide only positive or inconclusive results. In this circumstance, a true negative test result for an at-risk individual can only be obtained if another at-risk family member tests positive for a mutation.HNPCC Indications HNPCC is caused by germline mutation of
12、 the DNA mismatch repair genes (hMLH1, hMSH2, hPMS1, hPMS2, hMSH6). Microsatellite instability (MSI) is found in the colorectal cancer DNA (but not in the adjacent normal colorectal mucosa) of most individuals with germline mismatch repair gene mutations. Medical benefit of genetic testing in HNPCC,
13、 including MSI, is presumed but has not been established. Genetic testing in HNPCC is indicated for affected individuals in families meeting Amsterdam criteria (Table 2 of Technical Review),1 affected individuals meeting Bethesda criteria modified (Table 3 of Technical Review), and first degree adul
14、t relatives of those with known mutation (Figure 2). . Fig. 2. HNPCC gene testing.Appropriate strategy Genetic testing of both affected and at-risk individuals requires pretest genetic counseling and written informed consent. In combination with immunohistochemistry for hMSH2 and hMLH1, MSI testing
15、using the Bethesda markers should be performed on the tumor tissue of individuals putatively affected with HNPCC. A result of MSI-high in tumor DNA usually leads to consideration of germline testing by sequencing, confirmational sensitive gel electrophoresis (CSGE), or single-strand conformation pol
16、ymorphism (SSCP) for mutations in the hMSH2 and hMLH1 genes. Immunohistochemistry may direct which gene (hMSH2 or hMLH1) to target for germline analysis. If a deleterious mutation is found in an affected family member, then genetic testing in at-risk members will provide true positive or negative results. If no deleterious mutation is found in the affected person, only inconclusive results can be given to at-risk members as described above for FA
