Hereditary nonpolyposis colorectal cancer (lynch syndromes I and II). II. Biomarker studies

Nine families with the cancer family syndrome (CFS), or Lynch syndrome II, and two with hereditary site‐specific colonic cancer (HSSCC), or Lynch syndrome I, were investigated for the following potential biomarkers of genotype status: (1) in vitro tetraploidy of dermal fibroblast monolayer cultures; (2) tritiated thymidine uptake (3HdThd) labeling of colonic mucosa; (3) cytogenetics of peripheral blood mononuclear leukocytes; (4) quantitative serum immunoglobulin determinations; (5) methionine dependence in dermal fibroblasts in tissue culture; (6) segregation analysis; and (7) the study of gene linkage with respect to 25 landmark serum and blood group markers. Positive lod scores of 3.19 for linkage of the Jk (Kidd blood group) with CFS were obtained. Both in vitro tetraploidy and 3HdThd uptake in the distal colonic mucosal crypt compartments were positively associated with cancer risk status in CFS and HSSCC kindreds. There was a high incidence of polymorphisms of centromeric heterochromatin, including complete inversion. These findings are of particular clinical and genetic significance because HNPCC lacks premonitory signs of cancer risk. If confirmed, they could conceivably enable definition of genotype as early as birth in members of HNPCC kindreds, thereby enabling psychologic preparation and intensive cancer education for improved compliance in surveillance/management programs. These studies also provide new clues about the chromosome(s) bearing the presumed cancer gene(s). For example, CFS gene(s) may possibly be located on chromosome 2, where Jk is located. These biomarkers merit intensive study in additional HNPCC kindreds for a more complete assessment of their sensitivity and specificity. Additionally, essential aspects of previous reports involving biologic samples from these and/or similar subject kindreds are included to permit a comprehensive presentation of the combined findings of this consortium to date.