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

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...

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Veröffentlicht in:JNCI : Journal of the National Cancer Institute 2017-04, Vol.109 (4)
Hauptverfasser: Briollais, Laurent, Ozcelik, Hilmi, Xu, Jingxiong, Kwiatkowski, Maciej, Lalonde, Emilie, Sendorek, Dorota H, Fleshner, Neil E, Recker, Franz, Kuk, Cynthia, Olkhov-Mitsel, Ekaterina, Savas, Sevtap, Hanna, Sally, Juvet, Tristan, Hunter, Geoffrey A, Friedlander, Matt, Li, Hong, Chadwick, Karen, Prassas, Ioannis, Soosaipillai, Antoninus, Randazzo, Marco, Trachtenberg, John, Toi, Ants, Shiah, Yu-Jia, Fraser, Michael, van der Kwast, Theodorus, Bristow, Robert G, Bapat, Bharati, Diamandis, Eleftherios P, Boutros, Paul C, Zlotta, Alexandre R
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Sprache:eng
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Zusammenfassung: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.
ISSN:0027-8874
1460-2105
DOI:10.1093/jnci/djw258