Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia
Hereditary breast cancer accounts for 5-10% 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 BRCA1/2 genes. Hence, the genetic basis for a signif...
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| Veröffentlicht in: | PloS one 2021-01, Vol.16 (1), p.e0245362-e0245362 |
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| creator | Boujemaa, Maroua Hamdi, Yosr Mejri, Nesrine Romdhane, Lilia Ghedira, Kais Bouaziz, Hanen El Benna, Houda Labidi, Soumaya Dallali, Hamza Jaidane, Olfa Ben Nasr, Sonia Haddaoui, Abderrazek Rahal, Khaled Abdelhak, Sonia Boussen, Hamouda Boubaker, Mohamed Samir |
| description | Hereditary breast cancer accounts for 5-10% 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 BRCA1/2 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 BRCA 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 APC2, POU5F1, DOCK8, KANSL1, TMTC3 and the mismatch repair gene PMS2. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on APOBECA/B, UGT2B17 and GSTT1 genes. Whereas those disrupting SULT1A1 and UGT2B15 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. |
| doi_str_mv | 10.1371/journal.pone.0245362 |
| format | Article |
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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 BRCA1/2 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 BRCA 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 APC2, POU5F1, DOCK8, KANSL1, TMTC3 and the mismatch repair gene PMS2. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on APOBECA/B, UGT2B17 and GSTT1 genes. Whereas those disrupting SULT1A1 and UGT2B15 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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0245362</identifier><identifier>PMID: 33503040</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Bioinformatics ; Biology and Life Sciences ; Biomedical materials ; BRCA mutations ; BRCA1 Protein ; BRCA1 Protein - genetics ; BRCA2 Protein ; BRCA2 Protein - genetics ; Breast cancer ; Breast Neoplasms ; Breast Neoplasms - epidemiology ; Breast Neoplasms - genetics ; Cancer ; Copy number ; Copy number variations ; Deoxyribonucleic acid ; Disease ; DNA ; DNA Copy Number Variations ; Editing ; Etiology ; Family medical history ; Female ; Funding ; Gene expression ; Gene sequencing ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic aspects ; Genetic Predisposition to Disease ; Genetics ; Genomes ; Genomics ; Genotyping ; Germ-Line Mutation ; Health risks ; Hospitals ; Humans ; Laboratories ; Life Sciences ; Malignancy ; Medical prognosis ; Medicine ; Medicine and Health Sciences ; Middle Aged ; Military ; Mutation ; Oncology ; Oncology, Experimental ; Ovarian cancer ; Pathology ; Patients ; Population ; Prostate cancer ; Risk factors ; Skin cancer ; Tunisia ; Tunisia - epidemiology ; Visualization</subject><ispartof>PloS one, 2021-01, Vol.16 (1), p.e0245362-e0245362</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Boujemaa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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 BRCA1/2 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 BRCA 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 APC2, POU5F1, DOCK8, KANSL1, TMTC3 and the mismatch repair gene PMS2. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on APOBECA/B, UGT2B17 and GSTT1 genes. Whereas those disrupting SULT1A1 and UGT2B15 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.</description><subject>Adult</subject><subject>Bioinformatics</subject><subject>Biology and Life Sciences</subject><subject>Biomedical materials</subject><subject>BRCA mutations</subject><subject>BRCA1 Protein</subject><subject>BRCA1 Protein - genetics</subject><subject>BRCA2 Protein</subject><subject>BRCA2 Protein - genetics</subject><subject>Breast cancer</subject><subject>Breast Neoplasms</subject><subject>Breast Neoplasms - epidemiology</subject><subject>Breast Neoplasms - genetics</subject><subject>Cancer</subject><subject>Copy number</subject><subject>Copy number variations</subject><subject>Deoxyribonucleic acid</subject><subject>Disease</subject><subject>DNA</subject><subject>DNA Copy Number Variations</subject><subject>Editing</subject><subject>Etiology</subject><subject>Family medical history</subject><subject>Female</subject><subject>Funding</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Genes, BRCA1</subject><subject>Genes, BRCA2</subject><subject>Genetic aspects</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotyping</subject><subject>Germ-Line Mutation</subject><subject>Health risks</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Laboratories</subject><subject>Life Sciences</subject><subject>Malignancy</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Middle Aged</subject><subject>Military</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Oncology, Experimental</subject><subject>Ovarian cancer</subject><subject>Pathology</subject><subject>Patients</subject><subject>Population</subject><subject>Prostate cancer</subject><subject>Risk factors</subject><subject>Skin cancer</subject><subject>Tunisia</subject><subject>Tunisia - 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Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Boujemaa, Maroua</au><au>Hamdi, Yosr</au><au>Mejri, Nesrine</au><au>Romdhane, Lilia</au><au>Ghedira, Kais</au><au>Bouaziz, Hanen</au><au>El Benna, Houda</au><au>Labidi, Soumaya</au><au>Dallali, Hamza</au><au>Jaidane, Olfa</au><au>Ben Nasr, Sonia</au><au>Haddaoui, Abderrazek</au><au>Rahal, Khaled</au><au>Abdelhak, Sonia</au><au>Boussen, Hamouda</au><au>Boubaker, Mohamed Samir</au><au>Bandapalli, Obul Reddy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2021-01-27</date><risdate>2021</risdate><volume>16</volume><issue>1</issue><spage>e0245362</spage><epage>e0245362</epage><pages>e0245362-e0245362</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Hereditary breast cancer accounts for 5-10% 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 BRCA1/2 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 BRCA 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 APC2, POU5F1, DOCK8, KANSL1, TMTC3 and the mismatch repair gene PMS2. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on APOBECA/B, UGT2B17 and GSTT1 genes. Whereas those disrupting SULT1A1 and UGT2B15 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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>33503040</pmid><doi>10.1371/journal.pone.0245362</doi><tpages>e0245362</tpages><orcidid>https://orcid.org/0000-0002-2815-1834</orcidid><orcidid>https://orcid.org/0000-0002-8157-0544</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2021-01, Vol.16 (1), p.e0245362-e0245362 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2481581595 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Bioinformatics Biology and Life Sciences Biomedical materials BRCA mutations BRCA1 Protein BRCA1 Protein - genetics BRCA2 Protein BRCA2 Protein - genetics Breast cancer Breast Neoplasms Breast Neoplasms - epidemiology Breast Neoplasms - genetics Cancer Copy number Copy number variations Deoxyribonucleic acid Disease DNA DNA Copy Number Variations Editing Etiology Family medical history Female Funding Gene expression Gene sequencing Genes, BRCA1 Genes, BRCA2 Genetic aspects Genetic Predisposition to Disease Genetics Genomes Genomics Genotyping Germ-Line Mutation Health risks Hospitals Humans Laboratories Life Sciences Malignancy Medical prognosis Medicine Medicine and Health Sciences Middle Aged Military Mutation Oncology Oncology, Experimental Ovarian cancer Pathology Patients Population Prostate cancer Risk factors Skin cancer Tunisia Tunisia - epidemiology Visualization |
| title | Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia |
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