Study of Individuals and Families at High Risk for Cancer

OBJECTIVES:

- Identify individuals at high risk of cancer, especially due to personal or family
medical history.

- Evaluate and define clinical spectrum of disease in syndromes predisposing to cancer.

- Quantify risks of tumors in family members.

- Map, clone, and determine function of tumor susceptibility genes.

- Identify genetic determinants and gene-environmental interactions conferring cancer
risk in individuals and families.

- Evaluate gene-gene and gene-environmental interactions in tumor formation.

- Evaluate potential precursor states of disease in families at risk of cancer.

OUTLINE: One family member completes a family history questionnaire for verification of
diagnosis and construction of a family pedigree. Individuals and families undergo clinical
evaluation comprising at least a medical history, physical examination, and testing of blood
specimens. Other biologic specimens may also be obtained from some individuals, and some
individuals may undergo other diagnostic studies and examinations, depending on the type of
familial neoplasm being studied.

If a family is already participating in the study and a specific mutation in a tumor
predisposing gene predictive of disease has already been identified in the family,
individuals may be eligible for genetic testing. Genes tested include RB1, APC, BRCA1/2,
NF2, and VHL. Individuals under age 18 are only eligible to be tested for APC (familial
adenomatous polyposis), NF2 (neurofibromatosis type 2), PTCH (nevoid basal cell carcinoma
syndrome), RB1 (retinoblastoma), and VHL (von Hippel-Lindau disease).

Individuals may receive results of the genetic testing and genetic counseling is offered to
all individuals who are tested.

A certificate of confidentiality protecting the identity of research participants in this
project has been issued by the National Cancer Institute.

Families are followed every 1-2 years. In selected instances, individuals and families may
return to the Clinical Center periodically for study-specific follow-up evaluations.

PROJECTED ACCRUAL: A total of 7,500 individuals will be accrued for this study. Substudies,
involving subsets of the 7,500 individuals, are part of the overall study design.