{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T06:35:26Z","timestamp":1747204526979,"version":"3.40.5"},"posted":{"date-parts":[[2023,1,12]]},"group-title":"In Review","reference-count":41,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T00:00:00Z","timestamp":1673481600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,12,22]]},"abstract":"<title>Abstract<\/title>\n        <p>Prostate cancer (PrCa) is among the three top most frequent and deadlier cancers worldwide. The discovery of PARP inhibitors for the treatment of tumors having deleterious variants in homologous recombination repair (HRR) genes has placed PrCa in the roadmap of precision medicine. Still, the overall contribution of HRR genes for the 10-20% of the carcinomas arising in men with early-onset\/familial PrCa has not been fully clarified. We used Targeted Next Generation Sequencing (T-NGS) covering eight HRR genes (<italic>ATM<\/italic>, <italic>BRCA1<\/italic>, <italic>BRCA2<\/italic>, <italic>BRIP1<\/italic>, <italic>CHEK2<\/italic>, <italic>NBN<\/italic>, <italic>PALB2<\/italic> and <italic>RAD51C<\/italic>) and an analysis pipeline querying both small and large genomic variations, to clarify both their global and relative contribution for hereditary PrCa predisposition in a series of 462 early-onset\/familial PrCa cases. Deleterious variants were found in 3.9% of the patients, with <italic>CHEK2<\/italic> and <italic>ATM<\/italic> being the most frequently mutated genes (38.9% and 22.2% of the carriers, respectively), followed by <italic>PALB2<\/italic> and <italic>NBN<\/italic> (11.1% of the carriers, each), and then by <italic>BRCA2<\/italic>, <italic>RAD51C<\/italic>, and <italic>BRIP1<\/italic> (5.6% of the carriers each). Using the same NGS data, exonic rearrangements were found in two patients, one pathogenic in <italic>BRCA2<\/italic> and one of unknown significance in <italic>BRCA1<\/italic>. Additionally, 5.4% of the patients were carriers of variants of unknown significance (VUS). These results support the utility of T-NGS to clarify the genetic heterogeneity that underlies PrCa predisposition, allowing to detect both small and large genomic variations, and unveil <italic>CHEK2<\/italic> and <italic>ATM<\/italic> as the major HRR genes associated with early-onset and familial PrCa, respectively.<\/p>","DOI":"10.21203\/rs.3.rs-2403119\/v1","type":"posted-content","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T16:24:16Z","timestamp":1673540656000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic landscape of homologous recombination repair genes in early-onset\/familial prostate cancer patients"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4896-5982","authenticated-orcid":false,"given":"Manuel","family":"Teixeira","sequence":"first","affiliation":[{"name":"Portuguese Oncology Institute of Porto (IPO Porto)"}]},{"given":"Paula","family":"Paulo","sequence":"additional","affiliation":[{"name":"IPO Porto Research Center (CI-IPOP)"}]},{"given":"Marta","family":"Cardoso","sequence":"additional","affiliation":[{"name":"IPO Porto Research Center (CI-IPOP)"}]},{"given":"Andreia","family":"Brand\u00e3o","sequence":"additional","affiliation":[{"name":"IPO Porto Research Center (CI-IPOP)"}]},{"given":"Pedro","family":"Pinto","sequence":"additional","affiliation":[{"name":"IPO Porto Research Center (CI-IPOP)"}]},{"given":"Ariane","family":"Falconi","sequence":"additional","affiliation":[{"name":"IPO Porto Research Center (CI-IPOP)"}]},{"given":"Manuela","family":"Pinheiro","sequence":"additional","affiliation":[]},{"given":"Nuno","family":"Cerveira","sequence":"additional","affiliation":[{"name":"IPO Porto Research Center (CI-IPOP)"}]},{"given":"Rui","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Catarina","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Carla","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Peixoto","sequence":"additional","affiliation":[]},{"given":"Sofia","family":"Maia","sequence":"additional","affiliation":[]}],"member":"297","reference":[{"issue":"1","key":"ref1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.eururo.2019.08.005","article-title":"Recent global patterns in prostate cancer incidence and mortality rates","volume":"77","author":"Culp MBB","year":"2020","unstructured":"Culp MBB, Soerjomataram I, Efstathiou JA, Bray F, Jemal A. 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