We have demonstrated statistical evidence for a major gene in kindreds of childhood and adolescent soft tissue and bone sarcoma patients. To date, some of these kindreds that provide strong evidence for a major gene have been, found to have germline mutations in the tumor suppressor gene, p53. Statistical findings, however, suggest that a major gene may not account for all of the variation in cancer risk observed within or among kindreds. For example, siblings of probands are at greater risk of childhood cancer than siblings of parents; additional risk to relatives was observed in families of patients with embryonal rhabdomyosarcoma as compared to other histologic soft tissue sarcoma types; a significant multifactorial contribution in addition to a major gene was observed in the bone sarcoma kindreds. We therefore propose to determine the contribution of p53 germline mutations to the overall cancer risk using a strategy of combined linkage and segregation analysis. Initially we will be testing for linkage to p53 specifically. However, if the findings support involvement of other genetic loci, the strategy we have proposed could be generalized to identify other major genes or modifying genes. The immediate goals remain to identify the extent to which germline p53 mutations can account for the observed familial cancer aggregation in the sarcoma cohort. With this approach we can characterize the age-, sex- and site- specific penetrance for p53 germline mutations, the extent of phenocopies in the kindreds, and can identify any variation in risk not attributable to p53 as a major gene. In addition, we will determine the frequency of de novo mutations in p53, and the contribution of p53 germline mutations to the phenotype of a second malignant neoplasm. Findings from this project should provide sufficient information to develop guidelines for genetic testing of childhood sarcoma patients, guidelines for genetic counseling regarding the implications of a p53 germline mutation, and a framework from which to investigate the role of other genetic loci in familial cancer aggregates.
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