Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer
Pathogenic variants in known breast cancer (BC) predisposing genes explain only about 30% of Hereditary Breast Cancer (HBC) cases, whereas the underlying genetic factors for most families remain unknown. Here, we used whole-exome sequencing (WES) to identify genetic variants associated to HBC in 17...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-05-01
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| Series: | Frontiers in Genetics |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fgene.2018.00161/full |
| _version_ | 1818155240639168512 |
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| author | Giovana T. Torrezan Giovana T. Torrezan Fernanda G. dos Santos R. de Almeida Márcia C. P. Figueiredo Bruna D. de Figueiredo Barros Cláudia A. A. de Paula Renan Valieris Jorge E. S. de Souza Jorge E. S. de Souza Jorge E. S. de Souza Rodrigo F. Ramalho Felipe C. C. da Silva Elisa N. Ferreira Elisa N. Ferreira Amanda F. de Nóbrega Paula S. Felicio Maria I. Achatz Maria I. Achatz Sandro J. de Souza Sandro J. de Souza Sandro J. de Souza Edenir I. Palmero Edenir I. Palmero Dirce M. Carraro Dirce M. Carraro |
| author_facet | Giovana T. Torrezan Giovana T. Torrezan Fernanda G. dos Santos R. de Almeida Márcia C. P. Figueiredo Bruna D. de Figueiredo Barros Cláudia A. A. de Paula Renan Valieris Jorge E. S. de Souza Jorge E. S. de Souza Jorge E. S. de Souza Rodrigo F. Ramalho Felipe C. C. da Silva Elisa N. Ferreira Elisa N. Ferreira Amanda F. de Nóbrega Paula S. Felicio Maria I. Achatz Maria I. Achatz Sandro J. de Souza Sandro J. de Souza Sandro J. de Souza Edenir I. Palmero Edenir I. Palmero Dirce M. Carraro Dirce M. Carraro |
| author_sort | Giovana T. Torrezan |
| collection | DOAJ |
| description | Pathogenic variants in known breast cancer (BC) predisposing genes explain only about 30% of Hereditary Breast Cancer (HBC) cases, whereas the underlying genetic factors for most families remain unknown. Here, we used whole-exome sequencing (WES) to identify genetic variants associated to HBC in 17 patients of Brazil with familial BC and negative for causal variants in major BC risk genes (BRCA1/2, TP53, and CHEK2 c.1100delC). First, we searched for rare variants in 27 known HBC genes and identified two patients harboring truncating pathogenic variants in ATM and BARD1. For the remaining 15 negative patients, we found a substantial vast number of rare genetic variants. Thus, for selecting the most promising variants we used functional-based variant prioritization, followed by NGS validation, analysis in a control group, cosegregation analysis in one family and comparison with previous WES studies, shrinking our list to 23 novel BC candidate genes, which were evaluated in an independent cohort of 42 high-risk BC patients. Rare and possibly damaging variants were identified in 12 candidate genes in this cohort, including variants in DNA repair genes (ERCC1 and SXL4) and other cancer-related genes (NOTCH2, ERBB2, MST1R, and RAF1). Overall, this is the first WES study applied for identifying novel genes associated to HBC in Brazilian patients, in which we provide a set of putative BC predisposing genes. We also underpin the value of using WES for assessing the complex landscape of HBC susceptibility, especially in less characterized populations. |
| first_indexed | 2024-12-11T14:39:16Z |
| format | Article |
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| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-11T14:39:16Z |
| publishDate | 2018-05-01 |
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| series | Frontiers in Genetics |
| spelling | doaj.art-18405b7f3663462691d570e7fce4e2562022-12-22T01:02:01ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-05-01910.3389/fgene.2018.00161329368Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast CancerGiovana T. Torrezan0Giovana T. Torrezan1Fernanda G. dos Santos R. de Almeida2Márcia C. P. Figueiredo3Bruna D. de Figueiredo Barros4Cláudia A. A. de Paula5Renan Valieris6Jorge E. S. de Souza7Jorge E. S. de Souza8Jorge E. S. de Souza9Rodrigo F. Ramalho10Felipe C. C. da Silva11Elisa N. Ferreira12Elisa N. Ferreira13Amanda F. de Nóbrega14Paula S. Felicio15Maria I. Achatz16Maria I. Achatz17Sandro J. de Souza18Sandro J. de Souza19Sandro J. de Souza20Edenir I. Palmero21Edenir I. Palmero22Dirce M. Carraro23Dirce M. Carraro24Laboratory of Genomics and Molecular Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilNational Institute for Science and Technology in Oncogenomics and Therapeutic Innovation, São Paulo, BrazilLaboratory of Genomics and Molecular Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilLaboratory of Genomics and Molecular Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilLaboratory of Genomics and Molecular Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilLaboratory of Genomics and Molecular Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilLaboratory of Bioinformatics and Computational Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilInstituto de Bioinformática e Biotecnologia−2bio, Natal, BrazilInstituto Metrópole Digital, Federal University of Rio Grande do Norte, Natal, BrazilBioinformatics Multidisciplinary Environment, Federal University of Rio Grande do Norte, Natal, BrazilLaboratory of Genomics and Molecular Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilLaboratory of Genomics and Molecular Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilLaboratory of Genomics and Molecular Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilResearch and Development, Fleury Group, São Paulo, BrazilOncogenetics Department, A.C. Camargo Cancer Center, São Paulo, BrazilMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilOncogenetics Department, A.C. Camargo Cancer Center, São Paulo, Brazil0Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United StatesNational Institute for Science and Technology in Oncogenomics and Therapeutic Innovation, São Paulo, BrazilBioinformatics Multidisciplinary Environment, Federal University of Rio Grande do Norte, Natal, Brazil1Brain Institute, Federal University of Rio Grande do Norte, Natal, BrazilMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil2Barretos School of Health Sciences, Dr. Paulo Prata – FACISB, Barretos, BrazilLaboratory of Genomics and Molecular Biology, International Research Center, CIPE/A.C. Camargo Cancer Center, São Paulo, BrazilNational Institute for Science and Technology in Oncogenomics and Therapeutic Innovation, São Paulo, BrazilPathogenic variants in known breast cancer (BC) predisposing genes explain only about 30% of Hereditary Breast Cancer (HBC) cases, whereas the underlying genetic factors for most families remain unknown. Here, we used whole-exome sequencing (WES) to identify genetic variants associated to HBC in 17 patients of Brazil with familial BC and negative for causal variants in major BC risk genes (BRCA1/2, TP53, and CHEK2 c.1100delC). First, we searched for rare variants in 27 known HBC genes and identified two patients harboring truncating pathogenic variants in ATM and BARD1. For the remaining 15 negative patients, we found a substantial vast number of rare genetic variants. Thus, for selecting the most promising variants we used functional-based variant prioritization, followed by NGS validation, analysis in a control group, cosegregation analysis in one family and comparison with previous WES studies, shrinking our list to 23 novel BC candidate genes, which were evaluated in an independent cohort of 42 high-risk BC patients. Rare and possibly damaging variants were identified in 12 candidate genes in this cohort, including variants in DNA repair genes (ERCC1 and SXL4) and other cancer-related genes (NOTCH2, ERBB2, MST1R, and RAF1). Overall, this is the first WES study applied for identifying novel genes associated to HBC in Brazilian patients, in which we provide a set of putative BC predisposing genes. We also underpin the value of using WES for assessing the complex landscape of HBC susceptibility, especially in less characterized populations.http://journal.frontiersin.org/article/10.3389/fgene.2018.00161/fullcancer predisposition geneshereditary breast cancerwhole-exome sequencinggermline pathogenic variantscancer susceptibilityDNA repair genes |
| spellingShingle | Giovana T. Torrezan Giovana T. Torrezan Fernanda G. dos Santos R. de Almeida Márcia C. P. Figueiredo Bruna D. de Figueiredo Barros Cláudia A. A. de Paula Renan Valieris Jorge E. S. de Souza Jorge E. S. de Souza Jorge E. S. de Souza Rodrigo F. Ramalho Felipe C. C. da Silva Elisa N. Ferreira Elisa N. Ferreira Amanda F. de Nóbrega Paula S. Felicio Maria I. Achatz Maria I. Achatz Sandro J. de Souza Sandro J. de Souza Sandro J. de Souza Edenir I. Palmero Edenir I. Palmero Dirce M. Carraro Dirce M. Carraro Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer Frontiers in Genetics cancer predisposition genes hereditary breast cancer whole-exome sequencing germline pathogenic variants cancer susceptibility DNA repair genes |
| title | Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer |
| title_full | Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer |
| title_fullStr | Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer |
| title_full_unstemmed | Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer |
| title_short | Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer |
| title_sort | complex landscape of germline variants in brazilian patients with hereditary and early onset breast cancer |
| topic | cancer predisposition genes hereditary breast cancer whole-exome sequencing germline pathogenic variants cancer susceptibility DNA repair genes |
| url | http://journal.frontiersin.org/article/10.3389/fgene.2018.00161/full |
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