Suspected hereditary nonpolyposis colorectal cancer - International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) criteria and results of genetic diagnosis

PURPOSE: The aim of this study was to determine the frequency of mutations in the mismatch repair genes in families suspected of having hereditary non polyposis colorectal cancer. METHODS: We devised two criteria for families suspected of having hereditary nonpolyposis colorectal cancer (Criteria I a nd II). Criteria I consist of at least two first-degree relatives affected with colorectal cancer with at least one of the following. development of m ultiple colorectal tumors including adenomatous polyp, at least one colorec tal cancer case diagnosed before the age of 50, and occurrence of a heredit ary nonpolyposis colorectal cancer extracolonic cancer (endometrium, urinar y tract, small intestine, stomach, hepatobiliary system, or ovary) in famil y members. Criteria IT consist of one colorectal cancer patient with at lea st one of the following: early age of onset (<40 years); endometrial, urina ry tract, or small intestine cancer in the index patient or a sibling (one aged <50 years); and two siblings with other integral hereditary nonpolypos is colorectal cancer extracolonic cancers (one aged <50 years). A questionn aire was mailed to members of the International Collaborative Group on Here ditary Non-Polyposis Colorectal Cancer to determine the mutation detection rate in mismatch repair genes from the Families fulfilling these criteria. For comparison the mutation detection rare for families fulfilling the Amst erdam hereditary nonpolyposis colorectal cancer criteria in each institutio n was also obtained. RESULTS: Data were obtained from eight different insti tutions (in 7 different countries). In a total of 123 patients from 123 fam ilies (67 families fulfilling Criteria I and 56 families fulfilling Criteri a II), genetic testing for germline mismatch repair gene variants was perfo rmed. Germline mutations of the hMLH1 or hMSH2 genes were identified in 24 families (20 percent). Of these, the mutation detection rate for families f ulfilling Criteria I was 28 percent (19/67). The mutation detection rate fo r families fulfilling Criteria II was 9 percent (5/56). In these eight inst itutions, the overall mutation detection rate for families fulfilling the A msterdam hereditary nonpolyposis colorectal cancer criteria was 50 percent (77/154). CONCLUSION: The Criteria I for suspected hereditary nonpolyposis colorectal cancer have the advantages that they can be applied to nuclear f amilies and they can include extracolonic cancers. The results of this stud y suggest that families fulfilling Criteria I should be: offered genetic te sting. The relatively low mutation detection rate in those families fulfill ing Criteria II suggests that, using current techniques, genetic testing in these families is not practical.