Guy S. Schuelke

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). I. Clinical description of resource.

Hereditary nonpolyposis colorectal cancer (HNPCC) is comprised of the following: (1) the cancer family syndrome (CFS), or Lynch syndrome II, which shows early‐onset proximal colonic cancer predominance and other associated extracolonic adenocarcinomas, particularly endometrial carcinoma; and (2) hereditary site‐specific colon cancer (HSSCC), or Lynch syndrome I, which shows all of the same characteristics, except for extracolonic cancer. Nine families with CFS and two with HSSCC provided the resource that was tested for biomarkers (see companion article). All families were meticulously evaluated for genealogy and cancer verification. Biologic specimens were obtained during field visits to areas of closest geographic proximity to the families. Cancer education and recommendations for surveillance/management were provided to patients and their physicians. Additionally, 40 families (about 3000 individuals) with either CFS or HSSCC have been ascertained. Syndrome cancers were restricted to direct‐line relatives as opposed to nonbloodline relatives, arguing against involvement of environmntal factors. One documented clinical feature was a predilection for proximal versus distal colonic cancer in both CFS and HSSCC kindreds. This has important clinical significance in that it clarifies the need for instituting effective surveillance earlier to detect the predominantly proximal colonic cancers.

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.

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 (≤ 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.

Low serum IgA in a familial ovarian cancer aggregate

Abstract Low serum IgA levels were found to segregate in a sufficient number of individuals from a familial ovarian carcinoma aggregate to suggest that this may be a genetically determined immune defect etiologically integral to cancer susceptibility in this family. The putative role of IgA in pathogenesis remains elusive. Cancer-prone families should be thoroughly investigated for further elucidation of these phenomena.

Is cancer communicable

Recent developments in cancer epidemiology have led to the possibility of an exceedingly complex communicable factor(s) in cancer etiology. The transmission of such an agent(s) may require a susceptible genotype and/or other promotional events. Likely candidates which support this supposition include: Epstein-Barr virus (nasopharyngeal carcinoma, Burkitts lymphoma, salivary gland tumor among Eskimos, X-linked lymphoproliferative syndrome of Purtilo); human T-cell leukemia virus (adult T-cell leukemia); acquired immune deficiency syndrome (AIDS), complicated by Kaposis sarcoma (etiologic agent remains elusive, though epidemiology suggests possible infectious transmission); abnormal immune phenomena in households of Hodgkins disease patients; and clustering of various types of cancer in spouses, the general population, and families. We have selectively reviewed the literature and evolved an etiologic hypothesis which integrates a communicable agent(s) in concert with genetic and/or environmental carcinogenic interaction which could conceivably explain a significant fraction of the total cancer burden.

Mendelian Predisposition to Lymphomagenesis

More than 100 inherited cancer and precancer syndromes show simple Mendelian inheritance (81). Of the commonly occurring hereditary breast (82) or colon cancers (90), several differing genotypes give rise to the respective hereditary cancer syndromes. A voluminous literature on etiology of lymphomas is emerging linking genetics, immunology, and variable environmental factors.