ORIGINAL CONTRIBUTIONS The Kin-Cohort Study for Estimating Penetrance

A cross-sectional study may be more feasible than a cohort or case-control study for examining the effect of a genetic mutation on cancer penetrance outside of cancer families. The kin-cohort design uses volunteer probands selected from a population with a relatively high frequency of the mutations of interest. By considering the cancer risk in first-degree relatives of mutation-positive and-negative probands as a weighted average of the risk in carriers and noncarriers, with weights calculated assuming a known mode of inheritance, one can infer the penetrance of the mutations. The estimates of penetrance by age 70 years for three specific mutations in the BRCA1 and BRCA2 genes common among Ashkenazi Jews for the first occurrence of breast or ovary cancer is 63%. The kin-cohort design can be a useful tool for quickly estimating penetrance from volunteers in a setting in which the mutation prevalence is relatively high. Am J Epidemiol 1998; 148:623-30. biometry; breast neoplasms; colon neoplasms; epidemiologic methods; genetics; Jews; ovarian neoplasms Cohort and case-control designs are seldom feasible for estimating the penetrance of a rare mutation in a cancer gene, such as BRCA1 or BRCA2. To launch either a cohort study or a case-control study with adequate numbers of carriers who develop cancer poses daunting feasibility, economic, and ethical is-sues. Direct estimates of risk from studies of cancer-prone families, which often will have already been collected for linkage analysis and gene cloning, are likely to be too high. Modeling genotype conditional on phenotype (1) can estimate penetrance without ascertainment bias from high-risk families (1,2), but if the risk is higher in cancer families because of other genetic or environmental factors, the estimates may be too high for carriers in families with less cancer. In Received for publication February 3, 1997, and accepted fo