Familial heterogeneity of colon cancer risk.

The authors have assembled detailed family histories of cancer on 857 cancer probands, of whom 180 manifested colorectal carcinoma. This study determines if some families had a greater risk for colorectal cancer than others, and if so, what factors were associated with an increase in risk. To test for the possibility of heterogeneity of risk, a parameter called the Z-score, was calculated for each family. The Z-score is a measure of the number of cancer cases in the family adjusted for the number of expected cases. A permutation test was employed to test whether or not the variance of Z-scores from the sample was greater then expected by random chance. The variance for families ascertained through colon cancer probands, but not in any of the other groups, was significantly increased. Of the colon group, 10.6% fell into a high-risk category, as did 5.56% of the rectal cancer families, but only 3.95% of the other groups combined were at high risk. Anatomic sites (in the proband) with the highest Z-score variances were sigmoid and transverse colon, whereas lower variances were seen for cecum and descending colon. Risk status therefore may be partially dependent upon exact anatomic sites within the colon. The effect of proband's age of diagnosis was not significant, but did show the possibility of an effect on heterogeneity of risk for both the younger and older groups.

Genetics and smoking-associated cancers. A study of 485 families.

Cancer risk was evaluated in relatives of 254 consecutively ascertained probands with histologically verified lung cancer, and 231 probands with other smoking-related cancers. Findings disclosed a lack of any strong evidence for increased risk in lung cancer per se when only lung cancer in relatives was considered. Confounding factors, most prominent of which was the effect of cigarette smoking, variation of secular trends, and the heritability of the smoking phenotype itself, tended to obfuscate identification of an inherited effect presenting itself exclusively as lung cancer liability. On the other hand, a significant increase was observed in cancers of all anatomic sites among the relatives of lung cancer probands (P less than 0.001). Most of these neoplastic lesions were not associated with smoking and were not greatly influenced by secular trends. Furthermore, no significant excesses of cancer at all anatomic sites in relatives of probands with other smoking-associated carcinomas were observed. Thus, it may be concluded that the observation of increased risk for cancer at all anatomic sites in relatives of lung cancer probands may be a reflection of an underlying susceptibility to malignancy in these families.

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: 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.

Hereditary nonpolyposis colorectal cancer in a Navajo Indian family.

The purpose of this report is to describe a unique Navajo Indian kindred that manifests a tumor pattern consonant with hereditary nonpolyposis colorectal cancer (HNPCC). So far as we can determine this is the first report of HNPCC among American Indians.

Hereditary ovarian carcinoma. Biomarker studies.

Three ovarian-cancer-prone kindreds were studied, two of which contained identical twin sisters concordant for ovarian carcinoma. In one kindred, both identical twin sisters had daughters with ovarian carcinoma. In another kindred, one of the identical twin sisters had an ovarian-cancer-affected daughter. Ovarian carcinoma showed vertical transmission in all three families in a pattern consonant with an autosomal dominant mode of inheritance. Medical-genetic survey of each family included detailed questionnaires with retrieval of primary medical and pathology documents on cancer of all anatomic sites. Putative biomarker determinations included: (1) in vitro hyperdiploidy in dermal monolayer cultures; and (2) lower serum levels of alpha-L-fucosidase (less than or equal to 275 IU/ml) in all cancer-affected patients and statistically significant lower levels in 50% risk individuals when compared to spouse and published controls (P = 0.04 and P = 0.0002, respectively). These findings are discussed in context with the eventual development of a risk factor profile which, given acceptable sensitivity and specificity, would enable identification of individuals who would be prime candidates for intensive surveillance/management programs.