The Clinical Genetics Branch (CGB) integrates molecular and clinical observations in cancer genetics into an interdisciplinary approach involving epidemiologic, clinical, genetic, behavioral, statistical and laboratory methods to define the role of susceptibility genes in cancer etiology. The primary goal of this research program is translate recent dramatic advances in molecular genetics into evidence-based management strategies for persons at increased genetic risk of cancer. The central research strategy relies upon the detailed and meticulous assessment of the individual members of cancer-prone families. Hereditary Breast/Ovarian Cancer (HBOC) The first major clinical research project undertaken by CGB represents the next stage in DCEG's long-standing commitment to the study of hereditary breast and ovarian cancer (HBOC). The first priority with regard to these families has been to make clinical predictive genetic testing for BRCA1/2 mutations available to interested family members who had been previous participants in CGB research protocols (Protocol 02-C-0212). All families have been notified of their mutation status, and the process of bringing interested family members to the Clinical Center for genetic risk assessment, counseling, genetic testing and results disclosure is nearing completion. During the past year, 100 family members have undergone genetic risk assessment, and the majority of those have chosen genetic testing. At the present time, we have 60 hereditary breast/ovarian cancer families under active follow-up. Thirty-five carry deleterious mutations in BRCA1 or BRCA2, and two additional families are segregating the CHEK2 variant known as 1100delC. Thirty-one of the BRCA mutation-carrying families have been under active follow-up for more than 5 years (some as long as 35 years!), and this cohort is currently being analyzed to assess the prospective risks of breast, ovarian, fallopian tube and peritoneal cancers in a set of families that was offered risk-reducing surgery longer before the specific susceptibility genes had been cloned. Our BRCA mutation-negative families comprise a resource for evaluating new candidate highly penetrant breast cancer susceptibility genes. We recently evaluated two such genes (ZBRK1 and BRIP1), and found that neither contributed to the risk of breast and ovarian cancer in these families. DNA from the mutation-positive families is being contributed to an international collaboration which is seeking genetic modifiers of BRCA1 or BRCA2 penetrance. Our study of the prevalence of BRCA1/2 founder mutations in a series of 1000 Ashkenazi Israelis with prostate cancer during 1994 - 1995 documented a two-fold excess of prostate cancer among mutation carriers, providing additional evidence in support of the hypothesis that prostate cancer is part of the spectrum of BRCA-related cancers. No major differences in age at diagnosis or in histopathology between mutation-related and mutation-unrelated have been identified. These data were recently published. We have mounted a new set of psychosocial and behavioral research protocols for these same family members. These projects are addressing issues related to breast cancer screening, early diagnosis, behavioral, educational and psychosocial dynamics related to the process of genetic risk assessment and testing. Under consideration, but not yet implemented, are studies of endogenous hormones as contributors to the risk of hereditary breast cancer, and decision-making by family members related to the use of tamoxifen as a breast cancer chemoprevention strategy. This activity draws upon the expertise of our highly experienced staff, which includes a genetic counselor, a psychiatric social worker and a cancer genetics research nurse. These projects are being developed with the support of senior behavioral investigators from NCI's Division of Cancer Control and Population Studies, several of whom have joined CGB as Adjunct Investigators over the past year. Inherited Bone Marrow Failure Syndromes (IBMFS) Study Our multidisciplinary research program targeting the inherited pediatric disorders which predispose to bone marrow failure, acute leukemia and, in adult survivors, solid tumors is steadily accruing new patients. During its first 18 months, this study has enrolled 69 new families, with Fanconi's anemia and Diamond-Blackfan anemia representing the two most frequent disorders. (Protocol 02-C-0052). Fanconi's Anemia is the prototype of these diseases, which also include dyskeratosis congenita, Diamond-Blackfan syndrome and Schwachman-Diamond syndrome. These rare disorders are being used as models for studying mechanisms of carcinogenesis in humans. Analysis of survey data collected by Dr. Blanche Alter, this study's PI, has documented dramatic increases in cancer risk among FA patients, with O/E ratios of 50, 785, 4317, 2362 and 706 for all cancers, leukemia, vulvar cancer, esophageal and head/neck cancers respectively. These findings were published recently. In addition, we are analyzing the possible role of HPV in the etiology of the oral cavity and female genital malignancies which occur excessively in this setting. Genotype/phenotype correlations will be performed. An effort will be made to determine if persons who are heterozygous (carriers) for deleterious mutations in the FA genes are at increased risk of cancer. A number of interesting observations have emerged during the early stages of this study. We have encountered several instances of clinically normal family members (one from a family with Diamond-Blackfan anemia, the other from a dyskeratosis congenita kindred) who unexpectedly proved to carry their family's deleterious germline, disease-related mutation. This is likely to be an increasingly frequent occurrence as awareness of these rare disorders grows, and the availability of clinical mutation testing becomes more widespread. Analyses are underway (1) seeking a phenotypic predictor of subsequent cancer risk among patients with Fanconi's anemia (FA), (2) quantifying the risk of malignancy in a series of FA patients who have undergone bone marrow transplantation, and (3) evaluating the risk of leukemia among persons with severe congenital neutropenia who have been treated with white cell growth factors. A series of psychosocial and behavioral sub-studies has been built into the IBMFS project. These include: (a) an assessment of baseline genetic knowledge among study participants; (b) an evaluation of coping mechanisms among family members; and (c) a study of survivor guilt among unaffected siblings. Familial Testicular Cancer Over the past year, we have re-activated DCEG's interest in familial testicular cancer. We are actively collaborating with the International Testicular Cancer Linkage Consortium in a series of studies related to this rare familial cancer syndrome. CGB investigators have taken the lead in designing a central review of the testicular cancer pathology and a quantitative analysis of the occurrence of cancers other than germ cell tumors in the Consortium family set. Data collection related to these two projects should begin in late 2003. In addition, we our new protocol for new testicular cancer families has opened to patient accrual (Protocol 02-C-0178). During its first 6 months, this study has enrolled 69 new high-risk families, 39 of which are consented and under active evaluation.