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By reporting on the possible existence of a hereditary cancer and recommending further genetic evaluation, the pathologist can help identify families with hereditary cancer. Currently, however, recognition of a case of hereditary cancer relies predominantly on clinical criteria, as common cancers show only a few specific pathologic features that suggest hereditary predisposition. Furthermore, clinical criteria alone often fail to identify mutant gene carriers. In contrast to genes that have a high penetrance for causing cancer, such as BRCA1, APC, RET, and the mismatch repair genes, identifying carriers of mutant genes having a lower penetrance (as is the case for the BRCA2 gene) is more difficult. Studies to identify markers for mutant germline cancer-predisposing genes will typically require studying archival tissue specimens, but germline genetic testing on archival samples for research purposes is complicated by the need for patient consent unless specimens are stripped of their patient identifiers. Pathologists contemplating such research should seek informed consent for genetic testing prior to archiving tissues. The need for consent has led to concerns that certain types of cancer research projects will no longer be feasible; if patient consent has not been obtained, however, institutional review board-approved protocols that facilitate obtaining patient clinical data while maintaining patient confidentiality can overcome this problem. As clinical genetic testing for hereditary cancer becomes part of clinical practice, there are many concerns about the quality of service at each step in the process. One of the most important requirements for quality is to ensure that the performance of a genetic test is always linked to adequate pretest and posttest genetic counseling. Reporting of genetic test results should be standardized and include information about the technique used to identify mutations, the sensitivity and specificity of the test in detecting such mutations, and the limitations of the test. The report should also contain recommendations for further action and information packets to assist in the interpretation of the test. Pathologists have expertise in the area of laboratory proficiency testing and can play an important role in the establishment of a national proficiency program to ensure a quality genetic testing process. Cancer 1997; 80:636-48. © 1997 American Cancer Society.

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.

A medical genetic study has been undertaken of a large segment of an inbred Dutch kindred containing more than 2000 members. Noteworthy are occurrences of several hereditary precancerous diseases among the family members. These include two siblings with xeroderma pigmentosum and two siblings from another sibship who manifest a syndrome which may possibly be a variant of Fanconi's aplastic anemia. Four patients had histologically verified testicular malignant neoplasms. Other generally rarely occurring cancers included Wilms' tumor, thymic carcinoma, and astrocytoma. At present there is no satisfactory etiologic explanation for these events in this family. Environmental factors common to the family cannot be excluded. Hereditary factors conditioned strongly by consanguinity may be operating in concert with as yet unknown non-genetic factors such as an oncogenic virus.

Breast cancer risk factors are closely intertwined with the patient's cultural background, which may contribute to breast cancer aggregations within families. The difficult questions are: (1) does a truly hereditary breast cancer subset exist; (2) which familial aggregations are hereditary; and (3) is the hereditary form distinctive from its sporadic counterpart? These queries will be resolved once biomarkers are identified that show high sensitivity and specificity with genotype. The authors provide a review of this subject and will focus on their recent discovery of increased in vitro hyperdiploidy in cultured skin fibroblasts from patients with or at risk for hereditary breast cancer. The authors discuss findings from their study of family histories in 225 consecutively ascertained patients with verified breast cancer from the Creighton University School of Medicine Oncology Clinic. Findings consistent with an hereditary breast cancer syndrome were identified in 5% of the patients. Given the 112,000 new cases of breast cancer in the United States in 1982, the authors estimate that with a confidence coefficient of 0.95 between 2410 and 8790 of these individuals will manifest hereditary breast cancer. Specific surveillance/management programs should be geared to high-risk members of these families in which cancer yield will be predictable.

Breast cancer risk factors are closely intertwined with the patient's cultural background, which may contribute to breast cancer aggregations within families. The difficult questions are: (1) does a truly hereditary breast cancer subset exist; (2) which familial aggregations are hereditary; and (3) is the hereditary form distinctive from its sporadic counterpart? These queries will be resolved once biomarkers are identified that show high sensitivity and specificity with genotype. The authors provide a review of this subject and will focus on their recent discovery of increased in vitro hyperdiploidy in cultured skin fibroblasts from patients with or at risk for hereditary breast cancer. The authors discuss findings from their study of family histories in 225 consecutively ascertained patients with verified breast cancer from the Creighton University School of Medicine Oncology Clinic. Findings consistent with an hereditary breast cancer syndrome were identified in 5% of the patients. Given the 112,000 new cases of breast cancer in the United States in 1982, the authors estimate that with a confidence coefficient of 0.95 between 2410 and 8790 of these individuals will manifest hereditary breast cancer. Specific surveillance/management programs should be geared to high-risk members of these families in which cancer yield will be predictable.

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.