title: Hereditary prostate cancer as a feature of Lynch syndrome.
abstract: 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.
authors.affiliation: Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Bauer
authors.forename: Anna M
authors.initials: AM
authors.lastname: Ray
authors.forename: Bronwen A
authors.initials: BA
authors.lastname: Halstead-Nussloch
authors.forename: Robert G
authors.initials: RG
authors.lastname: Dekker
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Raymond
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Cooney
mesh_terms: D000328:Adult; D000368:Aged; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications* / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein