Clinical Genetic Studies of Familial and Hereditary Cancer Syndromes

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The Clinical Genetics Branch (CGB) is NCI's base for intramural clinical cancer genetics translational research activity. CGB brings a multidisciplinary, epidemiologic perspective to: Understanding the role of genes in the cause, treatment, and prevention of cancer; Developing comprehensive management strategies for high-risk individuals and families; and Training the next generation of clinical cancer genetics investigators. Hereditary Breast/Ovarian Cancer (HBOC) [CAS 8040] is based on a prospective cohort of 33 BRCA mutation-positive families with extensive clinical/epidemiologic data and biological samples [NCI Protocol #02-C-0212]. Research highlights include a series of important positive, and definitive-negative candidate gene studies analyzing genetic modifiers of BRCA1/2-related breast cancer risk as part of the Consortium of Investigators of Modifiers of BRCA1 (CIMBA) project, and a series of counseling/psychosocial reports of our early experience with HBOC families undergoing genetic risk assessment. With a mean prospective follow-up of 17.7 years for 395 mutation-negative family members, we observed no excess breast cancer risk compared with the general population. We are developing new laparoscopic tissue collection methods for in vivo collection of human ovarian surface epithelial cells for translational research purposes [CAS 10376], with very promising ovarian epithelial cell yields. Inherited Bone Marrow Failure Syndromes (IBMFS) Study [CAS 7130] targets Fanconi anemia (FA) and related disorders with a predilection for aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and selected solid tumors. This is the first epidemiologically-grounded, etiologically-focused investigation of these rare disorders. We enrolled 1400 members from 350 families. Major findings include quantitative estimates of FA- and dyskeratosis congenita (DC)-related cancer risks, identifying the striking similarity in cancer risks in these 2 disorders, expanding the clinical phenotype of these disorders, and identifying very short telomeres as pathognomonic for DC. Under a grant from the Fanconi Anemia Research Foundation, we are studying immune function in FA patients [CAS 10475]. We have collaboratively analyzed cancer risks in the the North American, German and Israeli FA cohorts, and reported similar data from the NCI cohort. We collaborated on development of an in vitro assay for pathogenicity of missense variants of unknown significance in FANCD1/BRCA2. We have analyzed the North American Diamond- Blackfan Registry (DBAR) and documented for the first time significant risks of cancer, particularly osteogenic sarcoma, in DBA. A closely-related project, Cancer in Rare Developmental Disorders [CAS 10549] is in its early stages of development. It leverages the observation that some oncogenes and tumor suppressor genes that are somatically altered in tumor tissue have also been found to be mutated in the germline of individuals with inherited conditions, e.g. Noonan (KRAS), Costello (HRAS) and Cowden syndromes (PTEN). Interdisciplinary dissection of such rare associations may lead to the focused identification of novel cancer genes. Thus, we will study rare developmental syndromes that are associated with cancer. Familial Testicular Cancer [CAS 7070, 7130] is an inadequately-studied familial cancer disorder being evaluated under 2 protocols, one accruing new multiple-case families [NCI Protocol #02-C-0178], the other aimed at mapping and cloning new TGCT susceptibility genes [NCI Protocol #04-C-N076]. Through the former, we have enrolled 609 consented members from 119 newly-ascertained families. This multidisciplinary, etiologically-oriented family study has found that testicular microlithiasis is more common than expected in TGCT kindred, recognized a possible new FTGCT syndrome characterized by renal and pituitary neoplasms, colonic polyps, lymphomas and lentigenes, and identified germline mutations in the PDE11A gene as modifier of FTGCT risk. We are the second largest contributor to International Testicular Cancer Linkage Consortium, through which we published a descriptive analysis of 469 TGCT families (containing 1002 TGCT cases), and documented that age-at-cancer-diagnosis is significantly younger in familial versus sporadic TGCT. Analyses of the histopathology of familial versus sporadic TGCT, and quantification of the risk of cancers other than TGCT in multiple-case families are nearing completion. As part of DCEGs Rare Cancers iSELECT project, we have confirmed strong associations between familial TGCT risk and 4 genomic regions recently implicated in GWAS analyses, i.e., KITLG, BAK1, DMRT1, and TERT-CLPTM1L. A family-based familial TGCT GWAS is under analysis, with a special focus on copy number variants. These data are also being pooled with those from a sporadic TGCT GWAS currently under analysis by colleagues in the Hormone and Reproductive Epidemiology Branch, DCEG. BR> The Li-Fraumeni Syndrome (LFS) [CAS 10503], originally identified by DCEG investigators 40 years ago is a rare, inherited disorder caused by germline TP53 mutations, with increased risks of early-onset bone and soft tissue sarcomas, breast, adrenal and brain cancer. After a long hiatus, we have initiated a new LFS study which will conduct comprehensive clinical evaluations, provide genetic counseling and testing, investigate cancer screening modalities, identify genetic modifiers, study cancer risk-reduction strategies, and search for the genetic etiology in the 30% of affected patients without a TP53 mutation. An international workshop is scheduled for November 2010, to launch the activities of a newly-formed consortium for the study of LFS, and to mobilize the LFS advocacy community. Familial Pleuropulmonary Blastoma (PPB) [CAS 10548] is a newly-described syndrome caused by germline mutations in DICER1; it represents the first known cancer predisposition syndrome caused by altered microRNA biogenesis. Leveraging an NIH Bench-to-Bedside award, we have formed a collaboration with the research group which made this remarkable observation, as a means to engage in the cutting-edge domain of miRNA research and introduce this technology into DCEG's research armamentarium. We will focus on more precisely defining the clinical phenotype of this remarkable disorder, in a new project that has just been submitted for IRB review. Neurofibromatosis 1 [CAS 10567] is a classic hereditary cancer susceptibility disorder. We are further defining its phenotype and seeking genetic modifiers of NF1 penetrance. Genetic Counseling, Psychosocial and Behavioral Studies in Familial Cancer is a vital component of CGB's research portfolio, which has yielded more than 30 peer-reviewed publications. A series of projects are actively underway as part of each familial cancer study being conducted by the Branch. We are developing new genetic counseling tools (e.g., the Colored Ecogenetics Relationship Map), applying novel analytic strategies, such as social network analysis, analyzing the variables associated with choosing surgery or screening in GOG-199, assessing determinants of bone marrow transplant decision-making within FA families, and exploring the impact of ambiguous screening test results on mood and screening behavior of BRCA1/2 mutation carriers.g., the Colored Ecogenetics Relationship Map), applying novel analytic strategies, such as social network analysis, analyzing the variables associated with choosing surgery or screening in GOG-199, assessing determinants of bone marrow transplant decision-making within FA families, and exploring the impact of ambiguous screening test results on mood and screening behavior of BRCA1/2 mutation carriers.