dc.contributor.author | Darst, BF | |
dc.contributor.author | Dadaev, T | |
dc.contributor.author | Saunders, E | |
dc.contributor.author | Sheng, X | |
dc.contributor.author | Wan, P | |
dc.contributor.author | Pooler, L | |
dc.contributor.author | Xia, LY | |
dc.contributor.author | Chanock, S | |
dc.contributor.author | Berndt, SI | |
dc.contributor.author | Gapstur, SM | |
dc.contributor.author | Stevens, V | |
dc.contributor.author | Albanes, D | |
dc.contributor.author | Weinstein, SJ | |
dc.contributor.author | Gnanapragasam, V | |
dc.contributor.author | Giles, GG | |
dc.contributor.author | Nguyen-Dumont, T | |
dc.contributor.author | Milne, RL | |
dc.contributor.author | Pomerantz, M | |
dc.contributor.author | Schmidt, JA | |
dc.contributor.author | Mucci, L | |
dc.contributor.author | Catalona, WJ | |
dc.contributor.author | Hetrick, KN | |
dc.contributor.author | Doheny, KF | |
dc.contributor.author | MacInnis, RJ | |
dc.contributor.author | Southey, MC | |
dc.contributor.author | Eeles, RA | |
dc.contributor.author | Wiklund, F | |
dc.contributor.author | Kote-Jarai, Z | |
dc.contributor.author | Conti, DV | |
dc.contributor.author | Haiman, CA | |
dc.date.accessioned | 2020-10-22T11:48:34Z | |
dc.date.issued | 2021-05-04 | |
dc.identifier.citation | Journal of the National Cancer Institute, 2020 | |
dc.identifier.issn | 0027-8874 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4190 | |
dc.identifier.eissn | 1460-2105 | |
dc.identifier.doi | 10.1093/jnci/djaa132 | |
dc.description.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 vs nonaggressive disease. METHODS: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 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 2-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive 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 nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on 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 = 3.71 × 10-4). 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. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | OXFORD UNIV PRESS INC | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.title | Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-08-20 | |
rioxxterms.versionofrecord | 10.1093/jnci/djaa132 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2020-08-27 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of the National Cancer Institute | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Oncogenetics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Oncogenetics | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Oncogenetics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Oncogenetics | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.publication-status | Published | |
pubs.embargo.terms | Not known | |
icr.researchteam | Oncogenetics | |
dc.contributor.icrauthor | Saunders, Edward | |
dc.contributor.icrauthor | Eeles, Rosalind | |
dc.contributor.icrauthor | Kote-Jarai, Zsofia | |