Germline Mutations in the Kallikrein 6 Region and Predisposition for Aggressive Prostate Cancer

Laurent Briollais; Hilmi Ozcelik; Jingxiong Xu; Maciej Kwiatkowski; Emilie Lalonde; Dorota H Sendorek; Neil E Fleshner; Franz Recker; Cynthia Kuk; Ekaterina Olkhov-Mitsel; Sevtap Savas; Sally Hanna; Tristan Juvet; Geoffrey A Hunter; Matt Friedlander; Hong Li; Karen Chadwick; Ioannis Prassas; Antoninus Soosaipillai; Marco Randazzo; John Trachtenberg; Ants Toi; Yu-Jia Shiah; Michael Fraser; Theodorus van der Kwast; Robert G Bristow; Bharati Bapat; Eleftherios P Diamandis; Paul C Boutros; Alexandre R Zlotta

doi:10.1093/jnci/djw258

Germline Mutations in the Kallikrein 6 Region and Predisposition for Aggressive Prostate Cancer

J Natl Cancer Inst. 2017 Apr 1;109(4). doi: 10.1093/jnci/djw258.

Authors

Laurent Briollais¹, Hilmi Ozcelik^{1

2

3}, Jingxiong Xu^{1

4}, Maciej Kwiatkowski^{5

6}, Emilie Lalonde^{7

8}, Dorota H Sendorek⁸, Neil E Fleshner⁹, Franz Recker⁵, Cynthia Kuk^{10

9}, Ekaterina Olkhov-Mitsel^{1

11

4}, Sevtap Savas¹², Sally Hanna¹⁰, Tristan Juvet⁹, Geoffrey A Hunter⁸, Matt Friedlander^{8

9}, Hong Li^{2

3}, Karen Chadwick⁹, Ioannis Prassas³, Antoninus Soosaipillai³, Marco Randazzo⁵, John Trachtenberg⁶, Ants Toi⁹, Yu-Jia Shiah⁸, Michael Fraser¹³, Theodorus van der Kwast¹⁴, Robert G Bristow^{7

13}, Bharati Bapat^{1

14}, Eleftherios P Diamandis³, Paul C Boutros^{7

15}, Alexandre R Zlotta^{1

10

9}

Affiliations

¹ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
² Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
³ Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
⁴ Dalla Lana School of Public Health, Toronto, ON, Canada.
⁵ Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland.
⁶ Department of Urology, Academic Hospital Braunschweig, Braunschweig, Germany.
⁷ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁸ Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
⁹ Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
¹⁰ Department of Surgery, Division of Urology, Mount Sinai Hospital, Toronto, ON, Canada.
¹¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹² Craig L. Dobbin Genetics Research Centre, Discipline of Genetics, Faculty of Medicine, Memorial University, St. John’s, NL, Canada.
¹³ Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
¹⁴ Department of Pathology, Toronto General Hospital, University Health Network. Toronto, ON, Canada.
¹⁵ Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.

PMID: 28376164
DOI: 10.1093/jnci/djw258

Abstract

Background: There is a need for markers that can specifically identify individuals at increased risk of harboring aggressive forms of prostate cancer (PCa).

Methods: 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.

Results: 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).

Conclusions: Our fine-mapping study has identified novel loci in the KLK 6 region strongly associated with aggressive PCa.

Publication types

Validation Study

MeSH terms

Aged
Chromosome Mapping
Disease-Free Survival
Genetic Predisposition to Disease*
Germ-Line Mutation
Haplotypes
Humans
Kallikreins / genetics*
Male
Middle Aged
Neoplasm Grading
Polymorphism, Single Nucleotide
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / pathology*

Substances

KLK6 protein, human
Kallikreins