{"doi":"10.1093/jnci/djaa132","title":"Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer","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.","journal":"JNCI Journal of the National Cancer Institute","year":2020,"id":56092,"datarank":0.6732954554598211,"base_score":4.48863636973214,"endowment":4.48863636973214,"self_citation_contribution":0.6732954554598211,"citation_network_contribution":0.0,"self_endowment_contribution":0.6732954554598211,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":88,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8049,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":291304,"name":"Tokhir Dadaev","orcid":"0000-0002-8268-0438","position":1,"is_corresponding":false},{"id":291305,"name":"Edward J. Saunders","orcid":"0000-0003-4343-3570","position":2,"is_corresponding":false},{"id":711,"name":"Xin Sheng","orcid":"0000-0002-6844-2740","position":3,"is_corresponding":false},{"id":291306,"name":"Peggy Wan","orcid":"0009-0002-3922-2746","position":4,"is_corresponding":false},{"id":291307,"name":"Loreall Pooler","orcid":"0000-0001-5388-6640","position":5,"is_corresponding":false},{"id":291308,"name":"Lucy Xia","orcid":"0000-0002-8805-6660","position":6,"is_corresponding":false},{"id":6431,"name":"Stephen J. Chanock","orcid":"0000-0002-2324-3393","position":7,"is_corresponding":false},{"id":21999,"name":"Sonja I. Berndt","orcid":"0000-0001-5230-0652","position":8,"is_corresponding":false},{"id":225522,"name":"Susan M. Gapstur","orcid":"0000-0002-1934-2110","position":9,"is_corresponding":false},{"id":291309,"name":"Victoria L. Stevens","orcid":"0000-0003-0259-4407","position":10,"is_corresponding":false},{"id":218606,"name":"Demetrius Albanes","orcid":"0000-0001-8330-4293","position":11,"is_corresponding":false},{"id":240083,"name":"Stephanie J. Weinstein","orcid":"0000-0002-3834-1535","position":12,"is_corresponding":false},{"id":13493,"name":"Vincent J. Gnanapragasam","orcid":"0000-0003-4722-4207","position":13,"is_corresponding":false},{"id":55326,"name":"Graham G. Giles","orcid":"0000-0003-4946-9099","position":14,"is_corresponding":false},{"id":291310,"name":"Tú Nguyen‐Dumont","orcid":"0000-0002-6217-0182","position":15,"is_corresponding":false},{"id":34653,"name":"Roger L. Milne","orcid":"0000-0001-5764-7268","position":16,"is_corresponding":false},{"id":293404,"name":"Mark M. Pomerantz","orcid":null,"position":17,"is_corresponding":false},{"id":291311,"name":"Julie A. Schmidt","orcid":"0000-0002-7733-8750","position":18,"is_corresponding":false},{"id":104569,"name":"Lorelei A. Mucci","orcid":"0000-0002-2551-4927","position":19,"is_corresponding":false},{"id":291312,"name":"William J. Catàlona","orcid":"0009-0004-2926-5114","position":20,"is_corresponding":false},{"id":36517,"name":"Kurt N. Hetrick","orcid":null,"position":21,"is_corresponding":false},{"id":6865,"name":"Kimberly F. Doheny","orcid":"0000-0001-8806-5738","position":22,"is_corresponding":false},{"id":291313,"name":"Robert J. MacInnis","orcid":"0000-0002-1627-5047","position":23,"is_corresponding":false},{"id":55360,"name":"Melissa C. Southey","orcid":"0000-0002-6313-9005","position":24,"is_corresponding":false},{"id":714,"name":"Rosalind A. Eeles","orcid":"0000-0002-3698-6241","position":25,"is_corresponding":false},{"id":240077,"name":"Fredrik Wiklund","orcid":"0000-0002-4623-0544","position":26,"is_corresponding":false},{"id":727,"name":"Zsofia Kote‐Jarai","orcid":"0000-0002-6329-5155","position":27,"is_corresponding":false},{"id":720,"name":"David V. Conti","orcid":"0000-0002-2941-7833","position":28,"is_corresponding":false},{"id":11270,"name":"Christopher A. Haiman","orcid":"0000-0002-0097-9971","position":29,"is_corresponding":false},{"id":11366,"name":"Burcu F. Darst","orcid":"0000-0002-6205-4632","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:05:49.581291Z","pmid":"32853339","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}