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Germline Mutations in the Kallikrein 6 Region and Predisposition for Aggressive Prostate Cancer.
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.
Afiliación
  • Briollais L; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • Ozcelik H; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • Xu J; Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • Kwiatkowski M; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
  • Lalonde E; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • Sendorek DH; Dalla Lana School of Public Health, Toronto, ON, Canada.
  • Fleshner NE; Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland.
  • Recker F; Department of Urology, Academic Hospital Braunschweig, Braunschweig, Germany.
  • Kuk C; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Olkhov-Mitsel E; Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
  • Savas S; Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
  • Hanna S; Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Juvet T; Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland.
  • Hunter GA; Department of Surgery, Division of Urology, Mount Sinai Hospital, Toronto, ON, Canada.
  • Friedlander M; Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Li H; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • Chadwick K; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
  • Prassas I; Dalla Lana School of Public Health, Toronto, ON, Canada.
  • Soosaipillai A; Craig L. Dobbin Genetics Research Centre, Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, NL, Canada.
  • Randazzo M; Department of Surgery, Division of Urology, Mount Sinai Hospital, Toronto, ON, Canada.
  • Trachtenberg J; Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Toi A; Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
  • Shiah YJ; Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
  • Fraser M; Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • van der Kwast T; Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • Bristow RG; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
  • Bapat B; Department of Surgical Oncology, Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Diamandis EP; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
  • Boutros PC; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
  • Zlotta AR; Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland.
J Natl Cancer Inst ; 109(4)2017 04 01.
Article en En | MEDLINE | ID: mdl-28376164
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Calicreínas / Predisposición Genética a la Enfermedad Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Aged / Humans / Male / Middle aged Idioma: En Revista: J Natl Cancer Inst Año: 2017 Tipo del documento: Article País de afiliación: Canadá
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Calicreínas / Predisposición Genética a la Enfermedad Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Aged / Humans / Male / Middle aged Idioma: En Revista: J Natl Cancer Inst Año: 2017 Tipo del documento: Article País de afiliación: Canadá