This is a proposal to investigate the effects of defective DNA mismatch repair in endometrial cancers. Defective DNA mismatch repair can be inherited as a Medelian train or can result from somatic mutation in one of a number of genes. Tumors with defective mismatch repair are characterized by numerous replication errors and are said to have an RER phenotype. Approximately 20% of endometrial cancers show RER. At present it is not known what proportion of RER-positive endometrial cancers arise in women with an inherited defect in a DNA mismatch repair gene, or whether somatic whether underlie most cases of RER in endometrial cancers. Similarly it is unknown whether RER-positive endometrial cancers behave differently than their DNA mismatch repair proficient counterparts. One of the specific objectives in this application is to identify the genetic determinant of defective DNA mismatch repair in endometrial cancers. A search for DNA mismatch repair gene mutations will be undertaken in a large series of RER-positive endometrial cancers. Mutations will be identified through investigations of both tumor DNA and mRNA. A second and related objective is to assess the heritability of endometrial cancers and defective mismatch repair in RER-positive tumors. The normal (constitutional) DNA of patients with mutation- positive tumors will be investigated to determine whether a mutation is inherited. Detailed family and medical histories will be obtained for a series of patients to determine what proportion of patients have a clinical or medical history consistent with inherited disease. Finally, we will investigate the effects of defective mismatch repair on endometrial cancer behavior. The hypothesis to be tested is that tumors with defective DNA mismatch repair progress in different ways than mismatch repair competent cancers. The effect of RER on tumor recurrence and patient survival will be evaluated. The relationship between defective mismatch repair and accumulation of mutations in oncogenes and tumor suppressor genes will also be investigated. These studies will serve to determine whether the RER phenotype is of prognostic significance in endometrial cancers and how it relates to tumorigenesis in general. The identification of inherited forms of endometrial cancers will have a positive impact on the patients and their at-risk family members. Identification of patients at-risk for cancers that are a feature of inherited disease will direct screening efforts. Earlier diagnosis and treatment will lead to increased patient survival.
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