{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T16:34:59Z","timestamp":1784219699615,"version":"3.55.0"},"reference-count":78,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T00:00:00Z","timestamp":1611705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004409","name":"Minist\u00e8re de l\u2019Enseignement Sup\u00e9rieur, de la Recherche Scientifique et des Technologies de l'Information et de la Communication","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004409","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004690","name":"Minist\u00e8re de la Sant\u00e9","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004690","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Hereditary breast cancer accounts for 5\u201310% of all breast cancer cases. So far, known genetic risk factors account for only 50% of the breast cancer genetic component and almost a quarter of hereditary cases are carriers of pathogenic mutations in<jats:italic>BRCA1\/2<\/jats:italic>genes. Hence, the genetic basis for a significant fraction of familial cases remains unsolved. This missing heritability may be explained in part by Copy Number Variations (CNVs). We herein aimed to evaluate the contribution of CNVs to hereditary breast cancer in Tunisia. Whole exome sequencing was performed for 9<jats:italic>BRCA<\/jats:italic>negative cases with a strong family history of breast cancer and 10 matched controls. CNVs were called using the ExomeDepth R-package and investigated by pathway analysis and web-based bioinformatic tools. Overall, 483 CNVs have been identified in breast cancer patients. Rare CNVs affecting cancer genes were detected, of special interest were those disrupting<jats:italic>APC2<\/jats:italic>,<jats:italic>POU5F1<\/jats:italic>,<jats:italic>DOCK8<\/jats:italic>,<jats:italic>KANSL1<\/jats:italic>,<jats:italic>TMTC3<\/jats:italic>and the mismatch repair gene<jats:italic>PMS2<\/jats:italic>. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on<jats:italic>APOBECA\/B<\/jats:italic>,<jats:italic>UGT2B17<\/jats:italic>and<jats:italic>GSTT1<\/jats:italic>genes. Whereas those disrupting<jats:italic>SULT1A1<\/jats:italic>and<jats:italic>UGT2B15<\/jats:italic>seem to correlate with good clinical response to tamoxifen. Our study revealed new insights regarding CNVs and breast cancer risk in the Tunisian population. These findings suggest that rare and common CNVs may contribute to disease susceptibility. Those affecting mismatch repair genes are of interest and require additional attention since it may help to select candidates for immunotherapy leading to better outcomes.<\/jats:p>","DOI":"10.1371\/journal.pone.0245362","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T18:28:21Z","timestamp":1611772101000},"page":"e0245362","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Germline copy number variations in BRCA1\/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia"],"prefix":"10.1371","volume":"16","author":[{"given":"Maroua","family":"Boujemaa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2815-1834","authenticated-orcid":true,"given":"Yosr","family":"Hamdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesrine","family":"Mejri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilia","family":"Romdhane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kais","family":"Ghedira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanen","family":"Bouaziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houda","family":"El Benna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumaya","family":"Labidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza","family":"Dallali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8157-0544","authenticated-orcid":true,"given":"Olfa","family":"Jaidane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Ben Nasr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abderrazek","family":"Haddaoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled","family":"Rahal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Abdelhak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamouda","family":"Boussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Samir","family":"Boubaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,27]]},"reference":[{"issue":"6","key":"pone.0245362.ref001","first-page":"394","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"F Bray","year":"2018","journal-title":"CA: a cancer journal for clinicians"},{"issue":"1","key":"pone.0245362.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ctrv.2014.10.008","article-title":"Beyond BRCA: new hereditary breast cancer susceptibility genes","volume":"41","author":"P Economopoulou","year":"2015","journal-title":"Cancer Treat Rev"},{"issue":"1","key":"pone.0245362.ref003","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1897-4287-12-15","article-title":"Expanding the genetic basis of copy number variation in familial breast cancer","volume":"12","author":"AL Masson","year":"2014","journal-title":"Hereditary cancer in clinical practice"},{"issue":"1","key":"pone.0245362.ref004","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13058-017-0825-6","article-title":"Increased genomic burden of germline copy number variants is associated with early onset breast cancer: Australian breast cancer family registry","volume":"19","author":"LC Walker","year":"2017","journal-title":"Breast Cancer Res"},{"issue":"3","key":"pone.0245362.ref005","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/nrg3871","article-title":"A copy number variation map of the human genome","volume":"16","author":"M Zarrei","year":"2015","journal-title":"Nat Rev Genet"},{"issue":"6","key":"pone.0245362.ref006","first-page":"809","article-title":"Next-Generation Sequencing-Based Detection of Germline Copy Number Variations in BRCA1\/BRCA2","volume":"19","author":"AY Schmidt","year":"2017","journal-title":"Validation of a One-Step Diagnostic Workflow. 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