B. Shannon Danes

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.

Occurrence of in vitro tetraploidy in the heritable colon cancer syndromes

Increased in vitro tetraploidy occurred in skin cultures derived from all affected patients and some family members at risk studied in families with heritable colon cancer syndromes (15 of 16 Gardner syndrome families, three Oldfield syndrome families, and four families with heritable colon cancer syndrome without polyposis coli) but was not present in all (one Gardner syndrome family, 16 of 19 familial polyposis coli families, and two Turcot syndrome families). Seven of 97 controls, family members by marriage, showed increased in vitro tetraploidy. None of these seven had a family history of colonic cancer but four had a family history of other solid tumors. Such in vitro studies illustrated that the occurrence of in vitro tetraploidy should be determined in families rather than individuals in order to determine whether all patients clinically affected show increased in vitro tetraploidy and vertical transmission that can be documented.

Increased in vitro tetraploidy: Tissue specific within the heritable colorectal cancer syndromes with polyposis coli

In vivo expressions of human hereditary tumors are known to be tissue specific; in familial polyposis coli the genotype is expressed solely as colonic polyps that become malignant and in the Gardner syndrome as extracolonic connective tissue tumors and related neoplasms in addition to such colonic lesions. In vitro such tissue specificity was also seen in these 2 syndromes. Increased tetraploidy has been observed only in those cultures derived from tissues, which although appearing normal in the patient, were known to undergo malignant transformation in vivo based on clinical phenotypes and family histories: colonic mucosa in familial polyposis coli, skin and colonic mucosa in the Gardner syndrome. Cultures established from tissues known not to show neoplastic growth or from benign tumors (fibromas, sebaceous cysts and lipomas) did not show increased tetraploidy. Increased tetraploidy in cultures established from these 2 syndromes did not identify all cultured cells with either mutant genotype or those cells showing abnormal benign growths in vivo but rather only in those that are known to undergo malignant transformation in vivo in both syndromes. Such observations suggested that in these 2 syndromes there was a population of tetraploid cells, at least in culture, constantly present which may be relevant to the multi‐step process of carcinogenesis.

A review of hereditary malignant melanoma including biomarkers in familial atypical multiple mole melanoma syndrome

This review provides a comprehensive coverage of hereditary malignant melanoma with emphasis upon its heterogeneity as well as newly developed biomarker investigations. The recently described familial atypical multiple mole melanoma (FAMMM) syndrome is featured. Particular attention has been given to findings of increased hyperdiploidy observed as an in vitro phenomenon in cultured skin fibroblasts from high-risk and FAMMM-affected subjects. The FAMMM genotype is complex in that it predisposes a patient not only to melanoma (cutaneous and intraocular malignant melanoma) but also to other histologic varieties of cancer, including cancer of the lung, pancreas, and breast. Attention is given to cancer surveillance and management programs for patients at increased risk for the several forms of hereditary malignant melanoma. This approach capitalizes advantageously upon employment of a knowledge of genetics and hereditary cancer syndrome identification, with particular attention to tumor associations.

Increased tetraploidy: Cell-specific for the gardner gene in the cultured cell

Human hereditary tumors in vivo are known to show tissue specificity. Increased endoreduplication with tetraploidy has been shown to occur in cultures established only from tissue containing epithelium (skin and colonic polyps) from patients with the Gardner syndrome. Cultures established from blood (short‐term lymphocyte and lymphoid suspension) and connective tissue (subcutaneous tissue, lipoma, mesentery, and sebaceous cyst) from the same patients did not show increased tetraploidy. These observations demonstrated that tetraploidy as an expression of the gene for the Gardner syndrome was cell‐specific in vitro and added further evidence that increased tetraploidy could be used for detection of the Gardner gene in families at risk.

The gardner syndrome. A study in cell culture

Tetraploidy was increased in skin fibroblast cultures derived from three probands with the Gardner syndrome and nine affected members of one family as compared to that occurring in cultures from five unaffected family members as well as from six relatives by marriage and 15 normals grown in the laboratory at the same time under the same conditions. Tetraploidy was present at the first subculture (2 weeks after the initial biopsy was cultured) and for each line studied the percentage of dividing cells showing tetraploidy remained constant. Increased occurrence of tetraploidy was not observed in skin fibroblast cultures from patients with the genetic disorders familial polyposis coli, familial osteomas, and familial fibromatosis (neurofibromatosis), each of which show one of the four abnormal tissue growths observed in the Gardner syndrome. The relationship of the observed tetraploidy to the increased risk of such patients to develop abnormal growths and cancer has not been established. The increased tetraploidy should be of value in identifying the presence of the gene for the Gardner syndrome in high risk families.

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.

Cystic fibrosis: Distribution of mucopolysaccharides in fibroblast cultures

Abstract The mucopolysaccharide content of skin fibroblast cultures from patients and heterozygous carriers of cystic fibrosis was increased as compared to that from normal, non-carrier individuals. The distribution of mucopolysaccharides in these cultures (with the intracellular uronic acid similar to control cells and that in the extracellular matrix and medium increased) was markedly different from that seen in cultures derived from normals and patients with Hurlers syndrome.