Laurent Briollais1, Hilmi Ozcelik1,2,3, Jingxiong Xu1,4, Maciej Kwiatkowski5,6, Emilie Lalonde7,8, Dorota H Sendorek8, Neil E Fleshner9, Franz Recker5, Cynthia Kuk10,9, Ekaterina Olkhov-Mitsel1,11,4, Sevtap Savas12, Sally Hanna10, Tristan Juvet9, Geoffrey A Hunter8, Matt Friedlander8,9, Hong Li2,3, Karen Chadwick9, Ioannis Prassas3, Antoninus Soosaipillai3, Marco Randazzo5, John Trachtenberg6, Ants Toi9, Yu-Jia Shiah8, Michael Fraser13, Theodorus van der Kwast14, Robert G Bristow7,13, Bharati Bapat1,14, Eleftherios P Diamandis3, Paul C Boutros7,15, Alexandre R Zlotta1,10,9. 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.
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.
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.
Authors: Jack Freeland; Preston D Crowell; Jenna M Giafaglione; Paul C Boutros; Andrew S Goldstein Journal: Cancer Lett Date: 2021-05-28 Impact factor: 8.679
Authors: Aram Vosoughi; Tuo Zhang; Kyrillus S Shohdy; Panagiotis J Vlachostergios; David C Wilkes; Bhavneet Bhinder; Scott T Tagawa; David M Nanus; Ana M Molina; Himisha Beltran; Cora N Sternberg; Samaneh Motanagh; Brian D Robinson; Jenny Xiang; Xiao Fan; Wendy K Chung; Mark A Rubin; Olivier Elemento; Andrea Sboner; Juan Miguel Mosquera; Bishoy M Faltas Journal: Nat Commun Date: 2020-12-03 Impact factor: 14.919