Rare Tumors and Cancer Predisposition in Individuals and Families

Study Description: The overall purpose of this study is to comprehensively and longitudinally evaluate the natural history of participants with rare tumors, genetic syndromes, genetic variants, and/or family history consistent with or hypothesized to contribute to predisposition to cancer(s) of interest to DCEG investigators. It will also facilitate evaluation of patients who may be candidates for other NIH Clinical Center (CC) clinical trials. These individuals and families will be evaluated and followed longitudinally to define the clinical spectrum (e.g., disease course, cancer risks, response to therapies, survival) and other phenotypic manifestations associated with rare tumors, genetic variants, and cancer predisposition syndromes. Objectives: 1. To evaluate and define the clinical spectrum (phenotype), penetrance and natural history of disease in syndromes predisposing to cancer; 2. To evaluate the phenotypes and natural history arising from known -or suspected- pathogenic germline variants in known -or suspected cancer-susceptibility genes; 3. To evaluate potential neoplastic precursor conditions in individuals and families at risk of cancer; 4. To quantify site-specific risks of such tumors in family members; 5. To discover, map, and determine inheritance patterns and functions of cancer susceptibility genes; 6. To identify etiologically or clinically relevant changes to the somatic genome in these patients; 7. To educate and counsel study participants about cancer risk including quantitative risk assessment and communication; prevention and surveillance recommendations; early detection activities; and management recommendations, when known. 8. To facilitate and enhance enrollment in interventional clinical trials within the NCI or other Institutes. Endpoints: Primary Endpoint: The general goals of the research conducted under this protocol are to: 1. Discover germline cancer susceptibility genes 2. Define the natural history and clinical spectrum of disease in high risk cancer susceptibility families 3. Define potential precursor states 4. Quantify risks of cancers in family members 5. Identify differences between familial and sporadic neoplasia 6. Identify genetic determinants, environmental risk factors, gene-environment, and gene-gene interactions in high risk families 7. Characterize the somatic genome of tumors from participants. Secondary Endpoints: 1. Define penetrance of tumors in family members 2. Create full protocols for specific tumors or syndromes based on the pilot studies conducing within this study