title: High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry.
abstract: The question of whether prostate cancer is part of the Lynch syndrome spectrum of tumors is unresolved. We investigated the mismatch repair (MMR) status and pathologic features of prostate cancers diagnosed in MMR gene mutation carriers. Prostate cancers (mean age at diagnosis = 62 ± SD = 8 years) from 32 MMR mutation carriers (23 MSH2, 5 MLH1 and 4 MSH6) enrolled in the Australasian, Mayo Clinic and Ontario sites of the Colon Cancer Family Registry were examined for clinico-pathologic features and MMR-deficiency (immunohistochemical loss of MMR protein expression and high levels of microsatellite instability; MSI-H). Tumor MMR-deficiency was observed for 22 cases [69 %; 95 % confidence interval (CI) 50-83 %], with the highest prevalence of MMR-deficiency in tumors from MSH2 mutation carriers (19/23, 83 %) compared with MLH1 and MSH6 carriers combined (3/9, 33 %; p = 0.01). MMR-deficient tumors had increased levels of tumor infiltrating lymphocytes compared with tumors without MMR-deficiency (p = 0.04). Under the assumption that tumour MMR-deficiency occurred only because the cancer was caused by the germline mutation, mutation carriers are at 3.2-fold (95 % CI 2.0-6.3) increased risk of prostate cancer, and when assessed by gene, the relative risk was greatest for MSH2 carriers (5.8, 95 % CI 2.6-20.9). Prostate cancer was the first or only diagnosed tumor in 37 % of carriers. MMR gene mutation carriers have at least a twofold or greater increased risk of developing MMR-deficient prostate cancer where the risk is highest for MSH2 mutation carriers. MMR IHC screening of prostate cancers will aid in identifying MMR gene mutation carriers.
authors.affiliation: Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology and Centre for Epidemiology and Biostatistics, University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Erin
authors.initials: E
authors.lastname: Mundt
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Melyssa
authors.initials: M
authors.lastname: Aronson
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Sally
authors.initials: S
authors.lastname: Pearson
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Rhiannon J
authors.initials: RJ
authors.lastname: Walters
authors.forename: Belinda N
authors.initials: BN
authors.lastname: Nagler
authors.forename: William J
authors.initials: WJ
authors.lastname: Crawford
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Ingrid
authors.initials: I
authors.lastname: Winship
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
mesh_terms: D000328:Adult; D000368:Aged; D003110:Colonic Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D015995:Prevalence; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics*; D012042:Registries