Hereditary prostate cancer as a feature of Lynch Syndrome
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Lynch Syndrome is an autosomal dominant condition characterized by early onset colorectal cancer (CRC) and is associated with cancers of the gastrointestinal and reproductive tracts. Germline mutations in DNA mismatch repair (MMR) genes have been causally associated with cancers of Lynch Syndrome. We investigated the occurrence of prostate cancer (PCa) in families with a history of colorectal cancer to assess prostate cancer as a feature of the Lynch Syndrome spectrum. Family pedigrees containing at least one CRC case as well as those meeting guidelines for Lynch Syndrome were identified and tumors were requested from participants who underwent radical prostatectomy (RP). Selected families were analyzed for association with type of PCa and clinical characteristics of aggressive disease. Microsatellite Instability (MSI) analysis was preformed on available tumors and correlated to loss of expression in MMR genes by immunohistochemical (IHC) staining. 95 individuals were identified as members of potential Lynch Syndrome families who underwent RP and 35 tumors from 31 families were received for MSI analysis. Two tumors from two unrelated families with known MMR mutations were MSI-high and one additional case from a third family was MSI-low. The remainder of the prostate cancer cases demonstrated no evidence of MSI. PCa incidence in families enriched for hereditary PCa with a history of Lynch Syndrome cancers is not strongly suggestive of the presence of an MMR mutation. However prostate tumors in known MMR mutation carriers did display MSI and loss of gene expression suggesting that PCa may arise in Lynch Syndrome due to defective DNA mismatch repair.
KeywordsLynch Syndrome Prostate cancer MMR mutations Microsatellite instability
Supported by a grant from the Donald and Jo Anne Petersen Endowed Research Fund of the University of Michigan Comprehensive Cancer Center. The University of Michigan Prostate Cancer Genetics Project (PCGP) is supported by the National Cancer Institute R01 CA79596 (K.A. Cooney). Funds were also provided from University of Michigan School of Public Health and the Public Health Genetics Interdepartmental Concentration Internship program. We thank all PCGP men and their families who generously volunteered their time to participate in our study. We also gratefully acknowledge Dr. Stephen N. Thibodeauau for his assistance with tumor staining and genetic testing of Patient 29 and Dr. Kirk Wojno for his assistance with pathology specimens.
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