A search for germline APC mutations in early onset colorectal cancer or familial colorectal cancer with normal DNA mismatch repair

Twenty percent of colorectal cancers (CRCs) arise in people who have a fami ly history of CRC in at least one other relative. Although a fraction of th ese CRCs are explained by two well-described autosomal dominant syndromes-5 % by hereditary nonpolyposis colorectal cancer (HNPCC) and 1% by familial a denomatous polyposis (FAP)-the cause of the remaining 14% of familial aggre gates of CRC is unknown. Many cases of HNPCC are due to germline mutations in DNA mismatch repair genes, leading to the tumor phenotype of microsatell ite instability (MSI), and most cases of FAP are caused by germline APC mut ations. To date, non-FAP familial CRC aggregates have not been evaluated fo r germline APC mutations. In this study, we examined the involvement of ger mline APC mutations in 79 individuals with CRC who had early-age onset of t heir cancer (age < 50 years) and/or a family history of CRC. Cases with FAP or HNPCC due to defective mismatch repair were excluded from the study. Us ing conformation-sensitive gel electrophoresis and the protein truncation t est as the screening methods, no functionally significant germline mutation s were detected for any of the cases. An apparently silent polymorphism res ulting in a 1-bp alteration of A --> G (proline --> proline) in exon 4 was observed. Additionally, four intervening sequence (IVS) alterations were de tected: IVS2-53t-->c in 3 cases; IVS4-17ins T in 3 cases; IVS5+32t-->c in 1 6 cases; and IVS5+33g-->a in 1 case. All appeared to be polymorphisms prese nt in similar proportions in an average-risk population. We conclude that g ermline APC mutations do not account for familial MSS (stable microsatellit e) CRC associated with few synchronous polyps. (C) 2001 Wiley-Liss, Inc.