{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T19:41:27Z","timestamp":1775590887311,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T00:00:00Z","timestamp":1663718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Hereditary prostate cancer (HPCa) has the highest heritability of any cancer in men. Interestingly, it occurs in several hereditary syndromes, including breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Several gene mutations related to these syndromes have been identified as biomarkers in HPCa. The goal of this study was to screen for germline mutations in susceptibility genes by using a multigene panel, and to subsequently correlate the results with clinical and laboratory parameters. This was undertaken in 180 HBOC families, which included 217 males with prostate cancer (PCa). Mutational analysis was further extended to 104 family members of mutated patients. Screening of HBOC families revealed that 30.5% harbored germline mutations in susceptibility genes, with 21.6% harboring pathogenic variants (PVs) and 8.9% having variants of uncertain significance (VUS). We found PVs at similar frequency in BRCA1 and BRCA2 genes (8.8% and 9.4%, respectively), while 0.56% of PVs were present in well-established susceptibility genes PALB2, TP53 and RAD51C. Moreover, 0.56% of monoallelic PVs were present in MUTYH, a gene whose function in tumorigenesis in the context of PCa is still unclear. Finally, we reported double heterozygosity (DH) in BRCA1\/2 genes in a single family, and found double mutation (DM) present in BRCA2 in a separate family. There was no significant difference between the mean age of onset of PCa in HBOC families with or without germline mutations in susceptibility genes, while the mean survival was highest in mutated patients compared to wild type. Furthermore, PCa is the second most recurrent cancer in our cohort, resulting in 18% of cases in both mutated and non-mutated families. Our investigation shows that PVs were located mostly in the 3\u2032 of BRCA1 and BRCA2 genes, and in BRCA2, most PVs fell in exon 11, suggesting a mutation cluster region relating to risk of HPCa. A total of 65 family members inherited the proband\u2019s mutation; of these, 24 developed cancer, with 41 remaining unaffected.<\/jats:p>","DOI":"10.3390\/genes13101692","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T01:47:06Z","timestamp":1663811226000},"page":"1692","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes"],"prefix":"10.3390","volume":"13","author":[{"given":"Giovanna","family":"D\u2019Elia","sequence":"first","affiliation":[{"name":"Unity of Clinical and Molecular Pathology, AOU, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gemma","family":"Caliendo","sequence":"additional","affiliation":[{"name":"Unity of Clinical and Molecular Pathology, AOU, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria-Myrsini","family":"Tzioni","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Albanese","sequence":"additional","affiliation":[{"name":"Unity of Clinical and Molecular Pathology, AOU, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luana","family":"Passariello","sequence":"additional","affiliation":[{"name":"Unity of Clinical and Molecular Pathology, AOU, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Maria","family":"Molinari","sequence":"additional","affiliation":[{"name":"Unity of Clinical and Molecular Pathology, AOU, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Teresa","family":"Vietri","sequence":"additional","affiliation":[{"name":"Unity of Clinical and Molecular Pathology, AOU, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,21]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Prostate cancer","volume":"7","author":"Rebello","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101927","DOI":"10.1016\/j.ctrv.2019.101927","article-title":"EAU-YAU Prostate Cancer Working Party. Hereditary prostate cancer\u2014Primetime for genetic testing?","volume":"81","author":"Heidegger","year":"2019","journal-title":"Cancer Treat. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Vietri, M., D\u2019Elia, G., Caliendo, G., Resse, M., Casamassimi, A., Passariello, L., Albanese, L., Cioffi, M., and Molinari, A. (2021). Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073753"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.semradonc.2016.08.002","article-title":"Prostate Cancer Genetics: Variation by Race, Ethnicity, and Geography","volume":"27","author":"Rebbeck","year":"2016","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5910","DOI":"10.1158\/1078-0432.CCR-18-0370","article-title":"Family History of Breast or Prostate Cancer and Prostate Cancer Risk","volume":"24","author":"Barber","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.cancergen.2020.04.074","article-title":"Double mutation of APC and BRCA1 in an Italian family","volume":"244","author":"Vietri","year":"2020","journal-title":"Cancer Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12032-021-01454-5","article-title":"Prevalence of mutations in BRCA and MMR genes in patients affected with hereditary endometrial cancer","volume":"38","author":"Vietri","year":"2021","journal-title":"Med. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1515\/cclm-2012-0154","article-title":"Identification of a novel in-frame deletion in BRCA2 and analysis of variants of BRCA1\/2 in Italian patients affected with hereditary breast and ovarian cancer","volume":"50","author":"Vietri","year":"2012","journal-title":"Clin. Chem. Lab. Med. (CCLM)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3892\/ijo.2021.5278","article-title":"DNA methylation and breast cancer: A way forward (Review)","volume":"59","author":"Vietri","year":"2021","journal-title":"Int. J. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1097\/JU.0000000000000137","article-title":"Bringing Prostate Cancer Germline Genetics into Clinical Practice","volume":"202","author":"Das","year":"2019","journal-title":"J. Urol."},{"key":"ref_11","first-page":"193","article-title":"SEOM clinical guidelines in hereditary breast and ovarian cancer (2019)","volume":"22","author":"Cajal","year":"2019","journal-title":"Clin. Transl. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1515\/cclm-2013-0263","article-title":"Double heterozygosity in the BRCA1 and BRCA2 genes in Italian family","volume":"51","author":"Vietri","year":"2013","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s10689-015-9786-z","article-title":"Analysis of PALB2 in a cohort of Italian breast cancer patients: Identification of a novel PALB2 truncating mutation","volume":"14","author":"Vietri","year":"2015","journal-title":"Fam. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.3892\/or.2014.3685","article-title":"A novel PALB2 truncating mutation in an Italian family with male breast cancer","volume":"33","author":"Vietri","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1002\/humu.20880","article-title":"Sequence variant classification and reporting: Recommendations for improving the interpretation of cancer susceptibility genetic test results","volume":"29","author":"Plon","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1200\/EDBK_238977","article-title":"The Role of BRCA Testing in Hereditary Pancreatic and Prostate Cancer Families","volume":"39","author":"Pilarski","year":"2019","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11912-020-0863-6","article-title":"Genetic Testing in Prostate Cancer","volume":"22","author":"Sokolova","year":"2020","journal-title":"Curr. Oncol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3105","DOI":"10.1002\/cncr.31316","article-title":"Genetic testing for hereditary prostate cancer: Current status and limitations","volume":"124","author":"Zhen","year":"2018","journal-title":"Cancer"},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/S1470-2045(21)00571-4","article-title":"Reimagining prostate cancer screening: The IMPACT of germline mutations","volume":"22","author":"Gandaglia","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/s10522-019-09824-3","article-title":"Genetic background, epigenetic factors and dietary interventions which influence human longevity","volume":"20","author":"Costa","year":"2019","journal-title":"Biogerontology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13148-021-01047-z","article-title":"Clinical epigenetics settings for cancer and cardiovascular diseases: Real-life applications of network medicine at the bedside","volume":"13","author":"Sarno","year":"2021","journal-title":"Clin. Epigenetics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.numecd.2009.03.006","article-title":"Interleukin-20 circulating levels in obese women: Effect of weight loss","volume":"20","author":"Maiorino","year":"2010","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1097\/00054725-200409000-00016","article-title":"Serum p53 antibodies in patients affected with ulcerative colitis","volume":"10","author":"Cioffi","year":"2004","journal-title":"Inflamm. Bowel. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1007\/s12020-015-0777-5","article-title":"Serum but not salivary cortisol levels are influenced by daily glycemic oscillations in type 2 diabetes","volume":"53","author":"Bellastella","year":"2016","journal-title":"Endocrine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1038\/s41436-020-0830-5","article-title":"Diagnosing hereditary cancer predisposition in men with prostate cancer","volume":"22","author":"Pritzlaff","year":"2020","journal-title":"Genet. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Vietri, M.T., Caliendo, G., D\u2019Elia, G., Resse, M., Casamassimi, A., Minucci, P.B., Ioio, C.D., Cioffi, M., and Molinari, A.M. (2020). Five Italian Families with Two Mutations in BRCA Genes. Genes, 11.","DOI":"10.3390\/genes11121451"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41525-022-00302-3","article-title":"An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance","volume":"7","author":"Iversen","year":"2022","journal-title":"npj Genom. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/s41436-020-00991-0","article-title":"Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance","volume":"23","author":"Lyra","year":"2020","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/sj.bjc.6605822","article-title":"UK Genetic Prostate Cancer Study Collaborators and BAUS Section of Oncology. Pros-tate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis","volume":"7","author":"Edwards","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1158\/0008-5472.CAN-19-1840","article-title":"Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness","volume":"80","author":"Patel","year":"2020","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.jmoldx.2017.05.001","article-title":"Validation of a Next-Generation Sequencing Pipeline for the Molecular Diagnosis of Multiple Inherited Cancer Predisposing Syndromes","volume":"19","author":"Paulo","year":"2017","journal-title":"J. Mol. Diagn."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"a003657","DOI":"10.1101\/mcs.a003657","article-title":"Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance","volume":"5","author":"Horak","year":"2019","journal-title":"Mol. Case Stud."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/s41391-020-00302-3","article-title":"TP53 alterations of hormone-na\u00efve prostate cancer in the Chinese population","volume":"24","author":"Liu","year":"2020","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Teroerde, M., Nientiedt, C., Duensing, A., Hohenfellner, M., Stenzinger, A., Duensing, S., Bott, S.R.J., and Ng, K.L. (2021). Revisiting the Role of p53 in Prostate Cancer. Prostate Cancer, Exon Publications. Chapter 8.","DOI":"10.36255\/exonpublications.prostatecancer.p53.2021"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"D\u2019Elia, G., Caliendo, G., Casamassimi, A., Cioffi, M., Molinari, A.M., and Vietri, M.T. (2018). APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation. Genes, 9.","DOI":"10.3390\/genes9070322"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Vietri, M.T., D\u2019Elia, G., Caliendo, G., Albanese, L., Signoriello, G., Napoli, C., and Molinari, A.M. (2022). Pancreatic Cancer with Mutation in BRCA1\/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation. Genes, 13.","DOI":"10.3390\/genes13020321"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1001\/jamaoncol.2018.6760","article-title":"Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines","volume":"5","author":"Nicolosi","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s00345-017-2122-5","article-title":"Men with family history of prostate cancer have a higher risk of disease recurrence after radical prostatectomy","volume":"36","author":"Thalgott","year":"2017","journal-title":"World J. Urol."},{"key":"ref_40","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_41","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_42","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/sj.bjc.6604453","article-title":"Rapid progression of prostate cancer in men with a BRCA2 mutation","volume":"99","author":"Narod","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12885-019-6055-9","article-title":"First-degree family history of breast cancer is associated with prostate cancer risk: A systematic review and meta-analysis","volume":"19","author":"Ren","year":"2019","journal-title":"BMC Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"103883","DOI":"10.1016\/j.ejmg.2020.103883","article-title":"BRCA and PALB2 mutations in a cohort of male breast cancer with one bilateral case","volume":"63","author":"Vietri","year":"2020","journal-title":"Eur. J. Med Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/JCO.19.02105","article-title":"Efficacy of Pembrolizumab in Patients with Noncolorectal High Microsatellite Instability\/Mismatch Repair\u2013Deficient Cancer: Results From the Phase II KEYNOTE-158 Study","volume":"38","author":"Marabelle","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Montisci, A., Vietri, M.T., Palmieri, V., Sala, S., Donatelli, F., and Napoli, C. (2021). Cardiac Toxicity Associated with Cancer Immunotherapy and Biological Drugs. Cancers, 13.","DOI":"10.3390\/cancers13194797"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"713694","DOI":"10.3389\/fcvm.2021.713694","article-title":"Severe Cardiac Toxicity Induced by Cancer Therapies Requiring Intensive Care Unit Admission","volume":"8","author":"Montisci","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1158\/2159-8290.CD-21-0007","article-title":"Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial","volume":"11","author":"Carreira","year":"2021","journal-title":"Cancer Discov."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/10\/1692\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:36:45Z","timestamp":1760143005000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/10\/1692"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,21]]},"references-count":48,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["genes13101692"],"URL":"https:\/\/doi.org\/10.3390\/genes13101692","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,21]]}}}