8b86b4b676489c11a74ff6bb634d186b pmc_33498765.pdf 2755504e5195521ec016075ad446c5e0aa66abeb pmc_33498765.pdf af1bf0b94978c9ab4844c6ce80173f8aeed216b071427b3ba5a868a460d30d59 pmc_33498765.pdf Title: BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort Subject: Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10–6.48; p = 1.16 10-5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10–7.70; p = 5.45 10-5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77–18.15; p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors. Keywords: BARD1; breast cancer; triple-negative breast cancer; ovarian cancer; hereditary breast and ovarian cancer; moderate cancer risk Author: Paula Rofes, Jesús Del Valle, Sara Torres-Esquius, Lídia Feliubadaló, Agostina Stradella, José Marcos Moreno-Cabrera, Adriana López-Doriga, Elisabet Munté, Rafael De Cid, Olga Campos, Raquel Cuesta, Álex Teulé, Èlia Grau, Judit Sanz, Gabriel Capellá, Orland Díez, Joan Brunet, Judith Balmaña and Conxi Lázaro Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Feb 26 02:55:57 2021 CET ModDate: Fri Feb 26 02:59:33 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 11 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 370853 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- OMNWBO+VnURWPalladioL Type 1 Custom yes yes no 10 0 XEMLIA+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 IPXSGW+URWPalladioL-BoldItal Type 1 Custom yes yes no 20 0 OMBSIN+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 AUUQHH+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 SOSCBV+CMSY10 Type 1 Builtin yes yes no 32 0 KEVZUZ+VnURWPalladioL-Bold Type 1 Custom yes yes no 36 0 KONDUX+EuphemiaUCAS-Bold Type 1C WinAnsi yes yes no 44 0 HIZBRM+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 47 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 69 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 73 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 77 0 CKBPVA+EURM10 Type 1 Builtin yes yes no 98 0 BCDEEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 113 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 02:49:38 CEST RepresentationInformation: pmc_33498765.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:08:40 CEST Size: 370853 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 284 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Patients and Controls Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: NGS Panel Testing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Variant Nomenclature Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Co-Segregation Analysis and Loss of Heterozygosity (LOH) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: gnomAD Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Info: Title: BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort Author: Paula Rofes, Jesús Del Valle, Sara Torres-Esquius, Lídia Feliubadaló, Agostina Stradella, José Marcos Moreno-Cabrera, Adriana López-Doriga, Elisabet Munté, Rafael De Cid, Olga Campos, Raquel Cuesta, Álex Teulé, Èlia Grau, Judit Sanz, Gabriel Capellá, Orland Díez, Joan Brunet, Judith Balmaña and Conxi Lázaro Subject: Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10 6.48; p = 1.16 10-5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10 7.70; p = 5.45 10-5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77 18.15; p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors. 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