Hereditary colorectal cancer: the French Canadian mutation spectrum. J. Jarry¹, G. Chong^1,2, I. Thiffault², S. McVety², S. Winocour¹, P.H. Gordon¹, G. Ouellette³, I. Gorska⁴, D. Farber^1,2, V. Marcus², R. Fodde⁵, P. Hutter⁶, W.D. Foulkes². 1) SMBD-Jewish General Hospital, Montreal, Canada; 2) McGill University, Montreal, Canada; 3) CHUS, Sherbrooke, Canada; 4) CHUM, Montreal, Canada; 5) Dept Pathology, Erasmus Medical Center, Rotterdam, the Netherlands; 6) Institut Central des Hôpitaux Valaisans, Sion, Switzerland.
   Colorectal cancer (CRC) ranks amongst the most frequent cancers worldwide and is the second leading cause of cancer-related deaths in the Western world. Inherited forms of CRC include hereditary non-polyposis colorectal cancer (HNPCC), caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2; familial adenomatous polyposis (FAP), caused by mutations in APC; and MYH-associated polyposis (MAP). The CRC mutation spectrum in the French Canadian (FC) population, a recently founded population in which many founder effects have been reported, remains poorly documented. We report our experience on the mutation screening of FC patients with hereditary CRC. Using a multimodal approach that includes testing for both DNA and RNA, we have successfully identified mutations in MLH1, MSH2, and MSH6 in FC families fulfilling the Amsterdam or Bethesda criteria for HNPCC. A total of 22 mutations have been identified of which half were caused by exon deletions. Four of these mutations were detected more than once, but pedigree analysis indicates the families are unrelated. Haplotype analysis indicates the presence of a founder effect for these recurrent mutations. An additional number of FC families were tested for FAP and a total of 16 distinct mutations were identified in the APC gene. Families, in which probands exhibited a phenotype compatible with the attenuated form of FAP but for which no APC mutation could be found, were screened for the two common European mutations in the gene MYH. Four individuals were identified as biallelic carriers of mutations in MYH. While the spectrum of CRC mutations is wide in French Canadians, an abundance of exon deletions and the presence of founder effects for HNPCC patients can be singled out as characteristics of this population at the molecular level.