Childhood cancer and the SBLA syndrome.

Two nuclear families showing characteristics of the SBLA syndrome are described wherein progeny of breast cancer-affected mothers manifested early childhood malignant neoplasms. These observations have led us to postulate a novel type genetic-environmental interactive model which incorporates Knudsen's "two-hit" hypothesis as a partial explanation for the exceedingly early onset of cancer in the subject progeny. Given the assumption that the first hit was germinal with transfer of the deleterious SBLA gene at conception, we postulate that the second or somatic-hit occurred early on in utero. This may have involved a complex mechanism of one or more factors including tumor cell products, tumor specific antigens, immunosuppression, de-repressed oncogene, or an activated oncogenic virus via a transplacental communicable phenomenon. The testing of this new hypothesis dealing with carcinogenesis in the SBLA syndrome should employ immunologicalgenetic parameters concurrently in fetuses and mothers.

Carcinoembryonic antigen (CEA) in the cancer family syndrome.

We present findings on plasma CEA in relatives and spouses from six kindreds manifesting the Cancer Family syndrome. The CEA distributions per se were transformed to square root CEA to correct for skewness and kurtosis. Significant effects of age and duration of smoking were adjusted for by linear regression. Relatives were classified as: 1) cancer patients, 2) individuals at high genetic cancer risk (one or more first-degree relatives affected, and 3) individuals at low genetic cancer risk (no first-degree relatives affected) for statistical comparisons. Unrelated spouses were also classified into corresponding groups according to their directline mate's status. Cancer patients and relatives at high genetic risk had significantly greater mean square root CEA than relatives at low genetic risk, and, surprisingly, unrelated spouses had mean levels of square root CEA which were similar to that in the corresponding cancer risk class of their direct-line mates. Our results suggest the existence of both a genetic and connubial effect on CEA, presumably due to a common environmental agent acting in concert with the degree of genetic predisposition to oncogenesis in this syndrome.

Genetic and pathologic findings in a kindred with hereditary sarcoma, breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma.

A familial cancer aggregation comprising sarcomas, brain tumors, leukemias, and carcinomas of breast, larynx, lung, adrenal, cortex, and other sites has been studied from a pathologic--genetic standpoint. Based upon sibships segregating for cancer, the genetic segregation parameter is estimated to be 45.6 +/- 11% which is compatible with that expected for a rare deleterious autosomal gene showing complete dominance. Pathologic review of 16 tumors by bright field microscopy revealed variable occurrences of intranuclear cytoplasmic invaginations, intranucleolar bodies, and acidophilic intracytoplasmic inclusions in eight lesions. Two tumors showed both intranuclear cytoplasmic invaginations and intranucleolar inclusions. Morphological findings coupled with the observed pattern and distribution of cancer in the subject kindred suggest that the cancer-prone genotype interacts with one or more exogenous factors in causing this familial tumor association.

Multiple primary cancers and prolonged survival: familial colonic and endometrial cancers.

We describe features of multiple cancers in a small kindred wherein a cluster of tumors affecting various anatomic sites has been observed among eight directline relatives. Three of these individuals have had two or more primary malignancies, and one woman showed a remarkable tolerance to invasive cancer, having had four histologically verified neoplasms (cancers of the ovary, endometrium, and colon, and myelogenous leukemia). The constellation of tumors occurring at an early age among relatives of the kindred supports a genetic etiology.

Familial cancer: implications for surgical management of high-risk patients.

Knowledge of familial/genetic information about cancer risk involving at least 100 disorders could be utilized profitably by surgeons in their daily practice. Familial cancer of the breast, ovary, and colon, malignant melanoma, and testicular feminization syndrome, and masculinizing Turner's syndrome are discussed. Biological markers, an area of emerging research interest, have been considered for their cancer control potential. Prophylactic surgical implications for certain familial cancer have been given.

Role of heredity in multiple primary cancer.

The occurrence of multiple primary malignant neoplasms characterizes virtually all varieties of hereditary cancer. This report focuses on this phenomenon in 11 families with the Cancer Family Syndrome (heritable adenocarcinomas of the colon and endometrium) and a single extended kindred with site-specific colon cancer. Of the 316 relatives with cancer in the 12 families, 68 (21.5%) had two or more primary malignancies and 59 (86.8%) of these multiple primaries involved the colon and/or endometrium. A pooled analysis of this resource revealed a consistent 3% risk for a second primary cancer in each year of survival following first onset. If a second primary occurs, the risk for a third is extremely high (6.9% per year), but shows a nonlinear trend with increasing survival following second onset. The high risk for development of extraprimary malignancies in patients from these kindreds indicates that careful consideration should be given to total removal of their principal target organs following the initial manifestation of cancer.

Familial cancer syndromes: a survey.

Several pre-malignant diseases are known to have a genetic etiology. This study focuses attention upon precancerous disorders wherein the mode of inheritance is either well established or wherein it remains unclear even though familial aggregation of the particular diseases have been amply documented. These conditions will be discussed as useful models for systematic investigations of the host etiologic component in carcinogenesis. Our survey of hereditary precancerous syndromes includes multiple polyposis of the coli, the multiple mucosal neuroma syndrome, the Cancer Family Syndrome, Sipple's syndrome, Von Recklinghausen's neurofibromatosus, the multiple nevoid basal cell carcinoma syndrome, tuberous sclerosis, familial cutaneous malignant melanoma, and carcinoma of the breast. We have emphasized the heterogeneous character of many forms of familial cancer. Familial breast cancer associations clearly show such heterogeneity, as do colon cancer syndromes. Certain of these precancerous states are characterized by phenotypes which are clinically apparent, polyposis coli being the classic example. Others, such as Sipple's syndrome are amenable to routine screening for biochemical markers. The bulk of putative genetic cancer-predisposing problems require further basic investigation of modes of inheritance. Cancer control may be enhanced through communication of useful genetic and diagnostic information to primary care physicians. Referral of cancer clusters of possible genetic etiology from clinicians to human geneticists facilitates the necessary basic research.

The surgeon, genetics, and cancer control: the Cancer Family Syndrome.

A family manifesting the Cancer Family Syndrome has been evaluated extensively from the medical and genetic standpoint. Findings of excess occurrence of carcinoma of the colon and endometrium, multiple primary cancer, early age of onset, and autosomal dominant mode of genetic transmission mandate a program of increased surveillance and cancer education. Prophylactic surgical implications are provided for certain of these enormously high cancer risk patients.

Management of hereditary site-specific colon cancer.

A family with site-specific colon cancer and discrete adenomatous colon polyps in certain members has provided a prototype for the study and clinical management of hereditary cancer. Analysis of this kindred showed an autosomal dominant mode of inheritance, early onset of cancer with predilection for the right colon, and frequent extraprimary cancers of the colon. Knowledge of these phenomena are critical to the management of this hereditary cancer syndrome. On our recommendation, two brothers of the family who were treated for colon cancer by hemicolectomy underwent prophylactic total colectomy. The resected colon from one of these patients had an occult adenocarcinoma in a villoglandular polyp.

Urinary mercury excretion and proteinuria in pathology laboratory staff.

The use of mercuric chloride as an histological fixative was associated with high environmental atmospheric concentrations of mercury vapour (up to 0-5 nmol/l) as well as mercury compounds (total Hg to 1-0 nmol/l). Technicians exposed to this environment showed increased urinary mercury (median value 265 nmol/24h) and protein outputs (median value 117 mg protein/24h). Routine control measures, ventilation and careful handling of mercuric chloride solutions, reduced the level of atmospheric mercury vapour levels to within acceptable limits (threshold limit values 0-01 mg/m3 (0-05 nmol/l) alkul compounds and 0-05 mg/m3 (0-25 nmol/l) for all forms except alkyl). This reduction was associated with the disappearance of trace proteinuria from the technicians' urine. Contamination of histology laboratories by mercuric chloride should be minimised.

Familial Hodgkin's disease and associated cancer. A clinical-pathologic study.

The etiology of Hodgkin's disease is complex, as is evident in studies suggesting the importance of horizontal transmission, occupational factors, racial and ethnic background, and familial, genetic factors, or both, including HL-A associations. The present study is of a remarkable kindred in which Hodgkin's disease was histologically verified in two sibships involving second-cousins related through maternal great-grandparents. Cancer of the lung, breast, endometrium, ovary, pancreas, and brain, as well as leukemia and Wilms' tumor, occurred in first and second-degree relatives of the Hodgkin's patients. HL-A haplotypes in patients with Hodgkin's disease in this family showed HL-AB5 or HL-ABW35, an association confirmed in other reports. The findings of associated malignant neoplasms in familial Hodgkin's disease, here and elsewhere in the literature, suggest that in the quest for etiology of Hodgkin's disease one must view the disorder eclectically, with a painstaking search for multiple etiologies, genetic and environmental.

Familial risk and cancer control.

An intensive study of the family history of cancer in 4,515 patients screened consecutively by a multiphasic mobile cancer detection unit showed, after age correction, that cancer had developed in 8.9% of the probands when there was one cancer in a single first-degree relative, 16.2% had cancer with two family members affected, and 27.4% had cancer when three or more family members had been affected. This constituted a significant correlation between family and personal histories of cancer in these patients. Extrapolation to the United States population with cancer-control implications are given.