Effects of measured susceptibility genes on cancer risk in family studies

Numerous family studies have been performed to assess the associations between cancer incidence and genetic and non-genetic risk factors and to quantitatively evaluate the cancer risk attributable to these factors. However, mathematical models that account for a measured hereditary susceptibility gene have not been fully explored in family studies. In this report, we proposed statistical approaches to precisely model a measured susceptibility gene fitted to family data and simultaneously determine the combined effects of individual risk factors and their interactions. Our approaches are structured for age-specific risk models based on Cox proportional hazards regression methods. They are useful for analyses of families and extended pedigrees in which measured risk genotypes are segregated within the family and are robust even when the genotypes are available only in some members of a family. We exemplified these methods by analyzing six extended pedigrees ascertained through soft-tissue sarcoma patients with p53 germ-line mutations. Our analyses showed that germ-line p53 mutations and sex had significant interaction effects on cancer risk. Our proposed methods in family studies are accurate and robust for assessing age-specific cancer risk attributable to a measured hereditary susceptibility gene, providing valuable inferences for genetic counseling and clinical management.