Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients

This paper presents the analysis of familial cancer data collected in a hospital-based study of 159 childhood soft-tissue-sarcoma patients. Two different statistical models detected excess aggregation of cancer, which could be explained by a rare dominant gene. For each kindred, we estimated the probability of the observed cancer distribution under the dominant-gene model and identified 12 families that are the most likely to be segregating the gene. Two of those families have confirmed germ-line mutations in the p53 tumor-suppressor gene. The relative risk of affection for children who are gene carriers was estimated to be 100 times the background rate. Females were found to have a slightly higher age-specific penetrance, but maternal and paternal lineages made equal contributions to the evidence in favor of the dominant gene. The proband's histology, ethnicity, and age at diagnosis were evaluated to determine whether any of these altered the probability of affection in family members. Only embryonal rhabdomyosarcoma was found to be a significant covariate under the dominant-gene model. While molecular genetic studies of familial cancer will eventually provide answers to the questions of genetic heterogeneity, age- and site-specific penetrance, mutation rates, and gene frequency, information from statistical models is useful for setting priorities and defining hypotheses.