BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort

Rofes, Paula; Valle, Jesús Del; Torres-Esquius, Sara; Feliubadaló, Lídia; Stradella, Agostina; Moreno-Cabrera, José Marcos; López-Dóriga, Adriana; Munté, Elisabet; Cid, Rafael de; Campos, Olga; Cuesta, Raquel; Teulé, Àlex; Grau, Èlia; Sanz, Judit; Capellà, Gabriel; Dı́ez, Orland; Brunet, Joan; Balmañà, Judith; Lázaro, Conxi

doi:10.3390/genes12020150

Cited by 11 publications

(16 citation statements)

References 41 publications

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“…We have recently published a case–control study investigating the role of BARD1 in cancer predisposition in a Spanish HBOC cohort of 4015 individuals. The results supported a significant association of BARD1 PVs with hereditary breast cancer (OR = 4.18; CI = 2.10–7.70; p = 5.45 × 10 –5 ), particularly among triple-negative tumors (OR = 5.40; CI = 1.77–18.15; p = 0.001) 28 . However, it should be noted that only truncating and canonical splice site variants were considered for the risk calculations, whose prevalence in breast and/or ovarian cancer cases is very limited.…”

Section: Discussionsupporting

confidence: 65%

RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant

Rofes

Pineda

Feliubadaló

et al. 2021

Sci Rep

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Case–control studies have shown an association of BARD1 with hereditary breast and/or ovarian cancer (HBOC) predisposition. BARD1 alternatively spliced isoforms are abundant and some are highly expressed in different cancer types. In addition, a number of BARD1 germline pathogenic variants have been reported among HBOC patients. In previous reports, BARD1 c.1977A>G variant has been classified as pathogenic since it produces a frameshift transcript lacking exons 2 to 9. In the present study, we sought to validate the mRNA splicing results previously published and to contribute with new evidence to refine the classification of this substitution according to ACMG/AMP guidelines. The presence of the variant was screened in patients and controls. RT-PCR was performed in order to compare the transcriptional profiles of two variant carriers and ten non-carrier controls. In addition, allele-specific expression was assessed. No differences in variant frequency were detected between patients and controls. The RNA assay confirmed the presence of the shorter transcript lacking exons 2–9, but it was detected both in carriers and non-carriers. Furthermore, allelic imbalance was discarded and no significant differences in the proportion of full-length and shorter transcript were detected between carriers and controls. The shorter transcript detected corresponds to BARD1 isoform η, constituted by exons 1, 10 and 11. Our results support that this transcript is a constitutive splicing product rather than an aberrant transcript caused by BARD1 c.1977A>G variant, and for this reason this variant should be considered as likely benign following ACMG/AMP guidelines.

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Section: Discussionsupporting

confidence: 65%

RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant

Rofes

Pineda

Feliubadaló

et al. 2021

Sci Rep

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“…Shimelis et al identified 25 individuals harboring BARD1 PVs (0.61%) and reported an OR of 5.92 for TNBC cases of African American and Caucasian populations [11]. Rofes et al identified ten BARD1 PV carriers from 680 TNBC patients (carrier frequency = 0.9%), resulting in an OR = 5.40 [60]. Similar observations were reported in other studies [61,62], indicating that BARD1 is a risk gene for TNBC.…”

Section: Tnbc and Non Brca-genessupporting

confidence: 54%

Identification of a novel pathogenic variant in PALB2 and BARD1 genes by a multigene sequencing panel in triple negative breast cancer in Morocco

Laraqui¹,

Cavaillé²,

Uhrhammer³

et al. 2021

J. Genomics

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Pathogenic variants (PVs) in BRCA genes have been mainly associated with an increasing risk of triple negative breast cancer (TNBC). The contribution of PVs in non-BRCA genes to TNBC seems likely since the processing of homologous recombination repair of double-strand DNA breaks involves several genes. Here, we investigate the susceptibility of genetic variation of the BRCA and non- BRCA genes in 30 early-onset Moroccan women with TNBC. Methods: Targeted capture-based next generation sequencing (NGS) method was performed with a multigene panel testing (MGPT) for variant screening. Panel sequencing was performed with genes involved in hereditary predisposition to cancer and candidate genes whose involvement remains unclear using Illumina MiSeq platform. Interpretation was conducted by following the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) criteria. Results: PVs were identified in 20% (6/30) of patients with TNBC. Of these, 16.7% (5/30) carried a BRCA PV [10% (3/30) in BRCA1 , 6.7% (2/30) in BRCA2 ] and 6.6% (2/30) carried a non- BRCA PV. The identified PVs in BRCA genes ( BRCA1 c.798_799delTT, BRCA1 c.3279delC, BRCA2 c.1310_1313del, and BRCA2 c.1658T>G) have been reported before and were classified as pathogenic. The identified founder PVs BRCA1 c.798_799del and BRCA2 c.1310_1313delAAGA represented 10% (3/30). Our MGPT allowed identification of several sequence variations in most investigated genes, among which we found novel truncating variations in PALB2 and BARD1 genes. The PALB2 c.3290dup and BARD1 c.1333G>T variants are classified as pathogenic. We also identified 42 variants of unknown/uncertain significance (VUS) in 70% (21/30) of patients with TNBC, including 50% (21/42) missense variants. The highest VUS rate was observed in ATM (13%, 4/30). Additionally, 35.7% (15/42) variants initially well-known as benign, likely benign or conflicting interpretations of pathogenicity have been reclassified as VUS according to ACMG-AMP. Conclusions: PALB2 and BARD1 along with BRCA genetic screening could be helpful for a larger proportion of early-onset TNBC in Morocco.

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“…Previously, another study investigated the presence of germline PVs within the BARD1 gene in the Spanish population 17 . Among 4015 patients with clinical suspicion of HBOC, they identified 19 PVs: 8 truncating, 1 splicing and 2 large deletion, ending up with a PV prevalence of 0.47% which approximately doubles the 0.22% reported by Couch et al and the 0.25% described by Suszynska and Kozlowski 16 , 30 , and triples the 0.13% of protein-truncating variants reported by Dorling et al and the 0.15% identified by Hu et al 4 , 5 .…”

Section: Discussionmentioning

confidence: 99%

“…Germline CNVs are recognized as the genetic cause of diverse hereditary pathologies, even though their detection via NGS is still challenging 32 . Only a few studies have characterized the CNV landscape within the BARD1 gene, having reported a total of 8 different large deletions so far in BC or OC patients 17 , 20 – 22 , 33 – 35 . In our study, we have detected the deletion of exon 1 and the deletion of the entire gene previously reported 20 , 21 and, what is more, we have identified for the first time exons 2–11, exon 9 and exons 10–11 deletions present in three BC cases.…”

Section: Discussionmentioning

confidence: 99%

“…However, to our knowledge, none of them has taken in account the whole spectrum of possible pathogenic variants (PV) in the gene. Regarding the Spanish population, only one study has investigated the prevalence of BARD1 PVs in an important number of patients, focusing on the region of Catalonia 17 . With the purpose of continuing to deepen our knowledge of the gene in breast and ovarian cancer predisposition, here we report a comprehensive mutational analysis of the BARD1 gene in a cohort of 1946 patients who fulfilled criteria to be tested for pathogenic mutations in the BRCA1/2 genes 18 from different regions of Spain.…”

Section: Introductionmentioning

confidence: 99%

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Apparent regional differences in the spectrum of BARD1 pathogenic variants in Spanish population and importance of copy number variants

Benito-Sánchez

Barroso

Fernández

et al. 2022

Sci Rep

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Only up to 25% of the cases in which there is a familial aggregation of breast and/or ovarian cancer are explained by germline mutations in the well-known BRCA1 and BRCA2 high-risk genes. Recently, the BRCA1-associated ring domain (BARD1), that partners BRCA1 in DNA repair, has been confirmed as a moderate-risk breast cancer susceptibility gene. Taking advantage of next-generation sequencing techniques, and with the purpose of defining the whole spectrum of possible pathogenic variants (PVs) in this gene, here we have performed a comprehensive mutational analysis of BARD1 in a cohort of 1946 Spanish patients who fulfilled criteria to be tested for germline pathogenic mutations in BRCA1 and BRCA2. We identified 22 different rare germline variants, being 5 of them clearly pathogenic or likely pathogenic large deletions, which account for 0.26% of the patients tested. Our results show that the prevalence and spectrum of mutations in the BARD1 gene might vary between different regions of Spain and expose the relevance to test for copy number variations.

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BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort

Cited by 11 publications

References 41 publications

RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant

RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant

Identification of a novel pathogenic variant in PALB2 and BARD1 genes by a multigene sequencing panel in triple negative breast cancer in Morocco

Apparent regional differences in the spectrum of BARD1 pathogenic variants in Spanish population and importance of copy number variants

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