HEREDITARY NONPOLYPOSIS COLON-CANCER - ANALYSIS OF LINKAGE TO 2P15-16PLACES THE COCA1 LOCUS TELOMERIC TO D2S123 AND REVEALS GENETIC-HETEROGENEITY IN 7 CANADIAN FAMILIES

Hereditary nonpolyposis colon cancer (HNPCC) is an autosomal dominant trait responsible for approximately 6% of colorectal cancers. Linkage of the HNPCC trait to the D2S123 locus on 2p15-16 has previously been reported in two families. This HNPCC locus is now designated ''COCA1.' ' We have tested seven Canadian HNPCC families, who have a variety of clinical presentations, for linkage to a panel of microsatellite polym orphisms in the vicinity of D2S123. One family was clearly linked to t he COCA1 locus (LOD = 4.21), and a second family is likely to be linke d (LOD = 0.92). In three families linkage was excluded. In the remaini ng two families the data were inconclusive. In the linked family, indi viduals with cancer of the endometrium or ureter share a common haplot ype with 12 family members with colorectal cancer. This supports the s uspected association between these extracolonic neoplasms and the HNPC C syndrome. In addition, five of the six individuals with adenomatous polyps (but no colorectal cancer) have the same haplotype as the affec ted individuals, while the sixth carries a recombination. One individu al with colorectal cancer carries a recombination that places the COCA 1 locus telomeric to D2S123. This study localizes the COCA1 gene to an 8-cM region that is consistent with the location of the hMSH2 gene. W e also confirm that families presently classified as HNPCC are genetic ally heterogeneous.