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: in vitro
tetraploidy of dermal fibroblast monolayer cultures; tritiated
thymidine uptake (3HdThd) labeling of colonic mucosa; cytogenetics of peripheral blood mononuclear leukocytes; quantitative serum
immunoglobulin determinations;
methionine dependence in dermal fibroblasts in tissue culture; segregation analysis; and 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.