{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:10:20Z","timestamp":1792015820030,"version":"4.4.0"},"reference-count":36,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>It has been shown that the pathogenic variants (PVs) of the DNA Damage Response (DDR) genes, whether of a germinal or somatic nature, represent a predictive biomarker of high sensitivity to treatment with inhibitors of the enzyme poly-ADP-ribose polymerase (PARP) in patients with hormone-resistant metastatic prostate cancer (HRPCa). Moreover, the detection of PVs of the Homologous Recombination Repair (HRR) genes in PCa patients can help to define the patient\u2019s prognosis and the choice of the therapeutic procedure. Among men with metastatic PCa, the frequency of PVs in HRR genes ranges from 11% to 33%, which is a significantly higher rate compared to non-metastatic PCa, where the incidence is between 5% and 10%. Next-Generation Sequencing (NGS) results were more commonly obtained from newly acquired somatic samples compared to archived samples (prostate biopsy or prostatectomy). We developed an experimental multidisciplinary prospective study in patients with a new diagnosis of high-risk PCa at biopsy. The aim was to evaluate the presence of PVs of different HRR genes in patients with the first diagnosis of PCa in relation to a metastatic or non-metastatic stage, tumor aggressiveness, and early risk of progression. Among 43 initial tumor samples from 22 patients, 25 samples from 12 patients were selected for library preparation based on their DNA concentration and quality. After the NGS, 14 different DNA variants were prioritized. Oncogenetic and likely oncogenetic variants were found in the ATM, BRCA1, PTEN, KMT2D, and CDH1 genes. Moreover, variants of uncertain significance were found in ATM, DDR2, FANCA, FOXA1, PLCB4, PTCH1, and RB1.<\/jats:p>","DOI":"10.3390\/biology14020117","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T09:01:13Z","timestamp":1737622873000},"page":"117","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Early Detection of the Pathogenetic Variants of Homologous Recombination Repair Genes in Prostate Cancer: Critical Analysis and Experimental Design"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0396-7981","authenticated-orcid":false,"given":"Irene","family":"Bottillo","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7899-8056","authenticated-orcid":false,"given":"Alessandro","family":"Sciarra","sequence":"additional","affiliation":[{"name":"Department \u201cMaterno Infantile e Scienze Urologiche\u201d, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Bevilacqua","sequence":"additional","affiliation":[{"name":"Department \u201cMaterno Infantile e Scienze Urologiche\u201d, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Gentilucci","sequence":"additional","affiliation":[{"name":"Department \u201cMaterno Infantile e Scienze Urologiche\u201d, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0502-7613","authenticated-orcid":false,"given":"Beatrice","family":"Sciarra","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutic Chemistry, University Sapienza, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Santarelli","sequence":"additional","affiliation":[{"name":"Department \u201cMaterno Infantile e Scienze Urologiche\u201d, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4873-3257","authenticated-orcid":false,"given":"Stefano","family":"Salciccia","sequence":"additional","affiliation":[{"name":"Department \u201cMaterno Infantile e Scienze Urologiche\u201d, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bacigalupo","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Pastacaldi","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Pia","family":"Ciccone","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2195-7955","authenticated-orcid":false,"given":"Laura","family":"De Marchis","sequence":"additional","affiliation":[{"name":"Department Oncology, University Sapienza, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Santini","sequence":"additional","affiliation":[{"name":"Department Oncology, University Sapienza, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio Massimo","family":"Magliocca","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Sapienza, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7231-2295","authenticated-orcid":false,"given":"Elisabetta","family":"Merenda","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Sapienza, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"Forte","sequence":"additional","affiliation":[{"name":"Urology Unit, Vannini Hospital, 00190 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6864-2574","authenticated-orcid":false,"given":"Paola","family":"Grammatico","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1200\/JCO.18.00358","article-title":"PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer","volume":"37","author":"Castro","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sciarra, A., Frisenda, M., Bevilacqua, G., Gentilucci, A., Cattarino, S., Mariotti, G., Del Giudice, F., Di Pierro, G.B., Viscuso, P., and Casale, P. (2023). How the Analysis of the Pathogenetic Variants of DDR Genes Will Change the Management of Prostate Cancer Patients. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010674"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8054","DOI":"10.3390\/curroncol30090584","article-title":"Is It Time to Anticipate the Use of PARP Inhibition in ProstateCancer Patients?","volume":"30","author":"Sciarra","year":"2023","journal-title":"Curr. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/humu.23818","article-title":"Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification","volume":"40","author":"Parsons","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.dnarep.2006.10.006","article-title":"Mammalian single-strand break repair: Mechanisms and links with chromatin","volume":"6","author":"Caldecott","year":"2007","journal-title":"DNA Repair"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrc2812","article-title":"PARP inhibition: PARP1 and beyond","volume":"10","author":"Rouleau","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1200\/JCO.2012.43.1882","article-title":"Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer","volume":"31","author":"Castro","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_8","unstructured":"(2024, April 10). European Urological Association (EAU) guidelines Prostate Cancer. Available online: https:\/\/uroweb.org\/guidelines\/prostate-cancer."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1158\/1078-0432.CCR-21-3940","article-title":"Tumor Genomic Testing for >4000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib)","volume":"28","author":"Hussain","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.eururo.2019.06.004","article-title":"Germline DNA Repair Gene Mutation Landscape in Chinese Prostate Cancer Patients","volume":"76","author":"Wei","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1056\/NEJMoa1603144","article-title":"Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer","volume":"375","author":"Pritchard","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_12","unstructured":"ICGC\/TCGA Pan-Cancer Analysis of Whole Genomes Consortium (2020). Pan-cancer analysis of whole genomes. Nature, 578, 82\u201393."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.eururo.2019.08.019","article-title":"Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers","volume":"76","author":"Page","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1200\/JCO.2015.65.7759","article-title":"Active surveillance for the management of localized prostate cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement","volume":"34","author":"Chen","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.eururo.2018.09.021","article-title":"Germline Mutations in ATM and BRCA1\/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer","volume":"75","author":"Carter","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.eururo.2014.10.022","article-title":"Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer","volume":"68","author":"Castro","year":"2015","journal-title":"Eur. Urol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41391-021-00397-2","article-title":"Prevalence and clinical impact of tumor BRCA1 and BRCA2 mutations in patients presenting with localized or metastatic hormone-sensitive prostate cancer","volume":"25","author":"Bernard","year":"2022","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/s41391-018-0086-1","article-title":"Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: Association of Gleason score and tumor stage","volume":"22","author":"Marshall","year":"2019","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_19","first-page":"597","article-title":"A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer","volume":"55","author":"Lang","year":"2019","journal-title":"Int. J. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kim, I.E., Kim, S., and Srivastava, A. (2019). Similar incidence of DNA damage response pathway alterations between clinically localized and metastatic prostate cancer. BMC Urol., 19.","DOI":"10.1186\/s12894-019-0453-9"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.eururo.2017.02.023","article-title":"Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer","volume":"72","author":"Annala","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.eururo.2018.01.035","article-title":"Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide","volume":"74","author":"Antonarakis","year":"2018","journal-title":"Eur. Urol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Carr, T.H., Adelman, C., Barnicle, A., Kozarewa, I., Luke, S., Lai, Z., Hollis, S., Dougherty, B., Harrington, E.A., and Kang, J. (2021). Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer. Cancers, 13.","DOI":"10.3390\/cancers13225830"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/S1470-2045(21)00757-9","article-title":"Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): A multicentre, open-label, phase 2 trial","volume":"23","author":"Smith","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1001\/jamaoncol.2017.4027","article-title":"Patient-Paired Sample Congruence Between 2 Commercial Liquid Biopsy Tests","volume":"4","author":"Torga","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.jmoldx.2016.10.002","article-title":"Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists","volume":"19","author":"Li","year":"2017","journal-title":"J. Mol. Diagn."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.gim.2022.01.001","article-title":"Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC)","volume":"24","author":"Horak","year":"2022","journal-title":"Genet Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1038\/s41467-024-46370-0","article-title":"CRISPR\/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam\/Cabs1 gene cluster expression","volume":"15","author":"Cai","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nature10006","article-title":"Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA","volume":"474","author":"Wang","year":"2011","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1172\/JCI122367","article-title":"Targeting FOXA1-mediated repression of TGF-\u03b2 signaling suppresses castration-resistant prostate cancer progression","volume":"129","author":"Song","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/nature11125","article-title":"The mutational landscape of lethal castration-resistant prostate cancer","volume":"487","author":"Grasso","year":"2012","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nrc2399","article-title":"Cellular mechanisms of tumour suppression by the retinoblastoma gene","volume":"8","author":"Burkhart","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1177\/03008916231225576","article-title":"Novel insights into RB1 in prostate cancer lineage plasticity and drug resistance","volume":"110","author":"Ma","year":"2024","journal-title":"Tumori J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.bbrc.2023.02.083","article-title":"Histone methyltransferase KMT2D promotes prostate cancer progression through paracrine IL-6 signaling","volume":"655","author":"Zhang","year":"2023","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.euros.2023.04.003","article-title":"Germline ATM mutations detected by somatic DNA sequencing in Lethal Prostate cancer","volume":"52","author":"Grochot","year":"2023","journal-title":"Eur. Urol. Open Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nrurol.2018.9","article-title":"Clinical implications of PTEN loss in prostate cancer","volume":"15","author":"Jamaspishvilli","year":"2018","journal-title":"Nat. Rev. Urol."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/2\/117\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:34:37Z","timestamp":1759919677000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/2\/117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,23]]},"references-count":36,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["biology14020117"],"URL":"https:\/\/doi.org\/10.3390\/biology14020117","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,23]]}}}