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Germline sequencing DNA repair genes in 5,545 men with aggressive and non-aggressive prostate cancer.
Darst, Burcu F; Dadaev, Tokhir; Saunders, Ed; Sheng, Xin; Wan, Peggy; Pooler, Loreall; Xia, Lucy Y; Chanock, Stephen; Berndt, Sonja I; Gapstur, Susan M; Stevens, Victoria; Albanes, Demetrius; Weinstein, Stephanie J; Gnanapragasam, Vincent; Giles, Graham G; Nguyen-Dumont, Tu; Milne, Roger L; Pomerantz, Mark; Schmidt, Julie A; Mucci, Lorelei; Catalona, William J; Hetrick, Kurt N; Doheny, Kimberly F; MacInnis, Robert J; Southey, Melissa C; Eeles, Rosalind A; Wiklund, Fredrik; Kote-Jarai, Zsofia; Conti, David V; Haiman, Christopher A.
Afiliação
  • Darst BF; Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, US.
  • Dadaev T; The Institute of Cancer Research, London, UK.
  • Saunders E; The Institute of Cancer Research, London, UK.
  • Sheng X; Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, US.
  • Wan P; Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, US.
  • Pooler L; Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, US.
  • Xia LY; Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, US.
  • Chanock S; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, US.
  • Berndt SI; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, US.
  • Gapstur SM; American Cancer Society, Atlanta, Georgia, US.
  • Stevens V; American Cancer Society, Atlanta, Georgia, US.
  • Albanes D; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, US.
  • Weinstein SJ; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, US.
  • Gnanapragasam V; Academic Urology Group, Department of Surgery and Oncology, University of Cambridge, Cambridge, UK.
  • Giles GG; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, AU.
  • Nguyen-Dumont T; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, AU.
  • Milne RL; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Victoria, AU.
  • Pomerantz M; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, AU.
  • Schmidt JA; Department of Clinical Pathology, The University of Melbourne, Victoria, AU.
  • Mucci L; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, AU.
  • Catalona WJ; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, AU.
  • Hetrick KN; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Victoria, AU.
  • Doheny KF; Dana Farber Cancer Institute, Boston, Massachusetts, US.
  • MacInnis RJ; University of Oxford, Oxford, UK.
  • Southey MC; Harvard University, Cambridge, Massachusetts, US.
  • Eeles RA; Northwestern University Feinberg School of Medicine, Chicago, Illinois, US.
  • Wiklund F; Center for Inherited Disease Research, Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, US.
  • Kote-Jarai Z; Center for Inherited Disease Research, Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, US.
  • Conti DV; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, AU.
  • Haiman CA; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Victoria, AU.
J Natl Cancer Inst ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32853339
ABSTRACT

BACKGROUND:

There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive versus non-aggressive disease.

METHODS:

Participants were 5,545 European-ancestry men, including 2,775 non-aggressive and 2,770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency<0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are two-sided.

RESULTS:

BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D BRCA2 alleles (OR = 3.19, 95% CI = 1.94 to 5.25, P = 8.58x10-7) and 0.65% of aggressive and 0.11% of non-aggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79x10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P=.02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than non-aggressive cases (carrier frequencies=14.2% versus 10.6%, respectively; P = 5.56x10-5). However, this difference was statistically non-significant (P=.18) upon excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI=-1,65 to 0.48, P = 3.71x10-4).

CONCLUSIONS:

Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo prognóstico Idioma: Inglês Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo prognóstico Idioma: Inglês Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos