HLA in breast cancer-prone families and the cancer family syndrome.
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Biomedical subjects
Publications and source records attributed to J Lynch.
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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.
Although breast carcinoma is the most frequently occurring cancer in American women and has been the subject of extensive epidemiologic investigation, little attention has been devoted to use of risk-factor information in its control. Six of our 52 breast-cancer-prone families have at least one woman who has manifested breast cancer at age 30 or earlier. One such family had two women with breast cancer before age 30, and at least ten others affected by age 50. Transmission of this lesion was consistent with autosomal-dominant mode of inheritance. Ages of onset indicated a notably early peak, in contrast with the expected pre- and post-menopausal peaks in findings of the New York State Tumor Resistry and others. Genetic and epidemiologic information should be utilized to control breast cancer in certain families.
The particular patterns of familial aggregations of cancer in the several families reported from our clinical resource suggest that multiple genotypes explain their diversity of cancer susceptibility. This knowledge could be of value in improving cancer control. We postulate that each particular genotype functions in concert with differential carcinogenic interactions, including a possible oncogenic virus, contributing to carcinogenesis in the susceptible patient. This reasoning is consistent with a concept of genetic heterogeneity as an explanation for familial carcinoma of the breast. This phenomenon is not unlike the current explanation for the genetics of the mucopolysaccaridoses, the lipidoses and several other major disorders of man which show genetic heterogeneity.
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Verified breast cancer was present in a father, his mother, and his daughter. His sone had a brain tumor (by history) and his grandson, (ehs sone of the affected daughter), had a histologically verified rhabdomyosarcoma. This familial aggregation of cancers (except for leukemia, which is absent) is consistent with a newly described familial breast cancer syndrome. A single pleiotropic, dominantly transmitted gene, possibly interacting with carcinogenic factors, such as an oncogenic virus, may be the cause. A cancer-control potential exists for tumor associations such as those exhibited in this kindred, as well as for other cancer genetic syndromes where careful consideration is given to all histologic varieties of cancer.
Actual HL-A typing has been performed on 115 members of cancer family N, a large kindred (over 1000 members ascertained) showing the findings consistent with the cancer family syndrome. In the cancer-prone line (branches C and D) of the family, 20 of 21 members with cancer had one HL-A haplotype, HL-A2-HL-A12 (relative odds = 6.30), including some decreased family members who had haplotypes assigned. Eleven of 12 family members with cancer in branches C and D, actually typed, had HL-A2-HL-A12 (relative odds = 6.06). The single exception showing cancer and another haplotype in branch D is a child of a family member with haplotype HL-A2-HL-A12.
Carcinoma of the colon was studied in Omaha-Douglas County, Nebraska (population 345,000). A total of 154 cases of colon cancer were diagnosed in 1964 (44.7/100,000). The frequency distribution of these patients in specific census tracts of this community was determined. Statistical analysis of the data showed a greater frequency of colon cancer in patients living in census tracts with higher average income. Colon cancer appears to be nonrandomly distributed with respect to the income and socioeconomic status of its victims, suggesting that hypotheses consistent with environmental variables--particularly those characterizing extremely high versus extremely low socioeconomic groups, including occupation, diet and other life patterns--should be pursued. All of these data have implications for cancer epidemiology, cancer control, and carcinogenesis.
This study comprises five cancer prone families with one or more occurrences of melanoma in context with a variety of other histologic types of cancer, including an excess of multiple primary malignant tumors. The genetic mode of transmission of cancer in each family was consistent with a dominant factor which has seemingly predisposed these patients to a general cancer diatheses. The tumor spectrum included malignant melanoma and cancers of the breast, gastrointestinal tract, lung and lymphoproliferative system. Recently, S1 and S2 antigens were noted to occur with malignant melanoma and the same variety of tumors which have occured in these five families.
Two large kindreds manifesting the "cancer family syndrome" have been studied. Genetic and biologic studies reveal markers which have important implications for cancer detection, control and prevention. Valuable markers may be found in the major histocompatibility system, HL-A. The presence of carcinoembryonic antigen and SV-40 viral transformation of skin fibroblasts are other possibly important markers. Relationships of the ABO blood groups to cancer are under intensive study, as is the hepatitis-associated antigen.
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