title: Germ-line mutations in mismatch repair genes associated with prostate cancer.
abstract: Genetic predisposition to prostate cancer includes multiple common variants with a low penetrance (single nucleotide polymorphisms) and rare variants with higher penetrance. The mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 are associated with Lynch syndrome where colon and endometrial cancers are the predominant phenotypes. The purpose of our study was to investigate whether germ-line mutations in these genes may be associated with prostate cancer. One hundred and six male carriers or obligate carriers of MMR mutations were identified. Nine had contracted prostate cancer. Immunohistochemical analysis was done on tumor tissue from eight of the nine tumors. Observed incidence, cumulative risk at 60 and 70 years of age, age of onset, and Gleason score were compared with expected as assessed from population-based series. Absence of gene product from the mutated MMR gene was found in seven of eight tumors. Expected number of prostate cancers was 1.52 compared with 9 observed (P < 0.01). Mean age of onset of prostate cancer was 60.4 years compared with 66.6 expected (P = 0.006); the number of men with a Gleason score between 8 and 10 was significantly higher than expected (P < 0.00001). Kaplan-Meier analysis suggested that cumulative risk by 70 years in MMR mutation carriers may be 30% (SE, 0.088) compared with 8.0% in the general population. This is similar to the high risk associated with BRCA2 mutations. To our knowledge, this study is the first to indicate that the MMR genes may be among the rare genetic variants that confer a high risk of prostate cancer when mutated.
authors.affiliation: Section for Inherited Cancer, Department of Medical Genetics, Rikshospitalet University Hospital, N-0310 Oslo, Norway.
authors.forename: Eli Marie
authors.initials: EM
authors.lastname: Grindedal
authors.forename: Pål
authors.initials: P
authors.lastname: Møller
authors.forename: Ros
authors.initials: R
authors.lastname: Eeles
authors.forename: Astrid Tenden
authors.initials: AT
authors.lastname: Stormorken
authors.forename: Inger Marie
authors.initials: IM
authors.lastname: Bowitz-Lothe
authors.forename: Stefan Magnus
authors.initials: SM
authors.lastname: Landrø
authors.forename: Neal
authors.initials: N
authors.lastname: Clark
authors.forename: Rune
authors.initials: R
authors.lastname: Kvåle
authors.forename: Susan
authors.initials: S
authors.lastname: Shanley
authors.forename: Lovise
authors.initials: L
authors.lastname: Maehle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005819:Genetic Markers; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D045643:DNA Repair Enzymes