title: Germline Mutations in the Kallikrein 6 Region and Predisposition for Aggressive Prostate Cancer.
abstract: There is a need for markers that can specifically identify individuals at increased risk of harboring aggressive forms of prostate cancer (PCa).
  
  
  
  We surveyed the Kallikrein ( KLK ) region ( KLK 1-15) for single-nucleotide polymorphisms (SNPs) associated with aggressive PCa (Gleason Score ≥ 8) in 1858 PCa patients. Discovery cohorts (Swiss arm of the European Randomized Study of Screening for PCa, n = 379; Toronto, Canada, n = 540) and a validation cohort (Prostate, Lung, Colorectal and Ovarian [PLCO] screening trial, n = 939) were analyzed. Fine-mapping within the KLK region was carried out by genotyping and imputation in the discovery cohort, whereas PLCO data were provided through database of Genotypes and Phenotypes ( dbGaP ). The influence of SNPs of interest on biochemical-free survival was evaluated in a cohort of localized PCa from the International Cancer Genome Consortium (ICGC; n = 130) analyzed with next-generation sequencing. Single- and multi-SNP association studies, as well as haplotype analyses, were performed. All statistical tests were two-sided.
  
  
  
  Several SNPs in very strong linkage disequilibrium in the KLK 6 region and located within the same haplotype (rs113640578, rs79324425, rs11666929, rs28384475, rs3810287), identified individuals at increased risk of aggressive PCa in both discovery (odds ratio [OR] = 3.51-3.64, 95% confidence interval [CI] = 2.01 to 6.36, P = 1.0x10 -5 -8.4x10 -6 ) and validation (OR = 1.89-1.96, 95% CI = 0.99 to 3.71, P = .04-.05) cohorts. The overall test of haplotype association was highly statistically significant in each cohort ( P = 3.5x10 -4 and .006, respectively) and in the three data sets combined ( P = 2.3x10 -5 ). These germline SNPs independently predicted relapse in the ICGC cohort (hazard ratio = 3.15, 95% CI = 1.57 to 6.34, P = .001).
  
  
  
  Our fine-mapping study has identified novel loci in the KLK 6 region strongly associated with aggressive PCa.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Briollais
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Hilmi
authors.initials: H
authors.lastname: Ozcelik
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Dalla Lana School of Public Health, Toronto, ON, Canada.
authors.forename: Jingxiong
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland.|Department of Urology, Academic Hospital Braunschweig, Braunschweig, Germany.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kwiatkowski
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.|Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Emilie
authors.initials: E
authors.lastname: Lalonde
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Dorota H
authors.initials: DH
authors.lastname: Sendorek
authors.affiliation: Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Fleshner
authors.affiliation: Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland.
authors.forename: Franz
authors.initials: F
authors.lastname: Recker
authors.affiliation: Department of Surgery, Division of Urology, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Kuk
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.|Dalla Lana School of Public Health, Toronto, ON, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Olkhov-Mitsel
authors.affiliation: Craig L. Dobbin Genetics Research Centre, Discipline of Genetics, Faculty of Medicine, Memorial University, St. John’s, NL, Canada.
authors.forename: Sevtap
authors.initials: S
authors.lastname: Savas
authors.affiliation: Department of Surgery, Division of Urology, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Sally
authors.initials: S
authors.lastname: Hanna
authors.affiliation: Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Tristan
authors.initials: T
authors.lastname: Juvet
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Hunter
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.|Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Matt
authors.initials: M
authors.lastname: Friedlander
authors.affiliation: Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Chadwick
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Prassas
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Antoninus
authors.initials: A
authors.lastname: Soosaipillai
authors.affiliation: Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Randazzo
authors.affiliation: Department of Urology, Academic Hospital Braunschweig, Braunschweig, Germany.
authors.forename: John
authors.initials: J
authors.lastname: Trachtenberg
authors.affiliation: Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Ants
authors.initials: A
authors.lastname: Toi
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Shiah
authors.affiliation: Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Fraser
authors.affiliation: Department of Pathology, Toronto General Hospital, University Health Network. Toronto, ON, Canada.
authors.forename: Theodorus
authors.initials: T
authors.lastname: van der Kwast
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.|Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Pathology, Toronto General Hospital, University Health Network. Toronto, ON, Canada.
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Diamandis
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.|Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Surgery, Division of Urology, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Zlotta
mesh_terms: D000368:Aged; D002874:Chromosome Mapping; D018572:Disease-Free Survival; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D007610:Kallikreins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: C103551:KLK6 protein, human; D007610:Kallikreins