Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

Alenezi, Wejdan M.; Fierheller, Caitlin T.; Recio, Neil; Tonin, Patricia N.

doi:10.3390/genes11080856

Cited by 31 publications

(29 citation statements)

References 163 publications

(277 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In relation to the latter, we have performed all analyses in breast cancer cell line MCF-7, and we have performed a sub-analysis in the TN breast cancer cell line MDA-MB-231, replicating findings ( Figure S3 ). Current data supports a shared heritability for ER-negative (or TN) breast cancer and ovarian cancer susceptibility [ 3 , 41 , 42 , 43 ]. Interestingly, epidemiological and molecular evidence indicates that high-grade serous ovarian cancer arises not from ovarian epithelial cells, but from cells in the fimbriae of the fallopian tubes [ 44 ].…”

Section: Discussionmentioning

confidence: 66%

RAD51D Aberrant Splicing in Breast Cancer: Identification of Splicing Regulatory Elements and Minigene-Based Evaluation of 53 DNA Variants

Bueno-Martínez

Sanoguera-Miralles

Valenzuela-Palomo

et al. 2021

Cancers

View full text Add to dashboard Cite

RAD51D loss-of-function variants increase lifetime risk of breast and ovarian cancer. Splicing disruption is a frequent pathogenic mechanism associated with variants in susceptibility genes. Herein, we have assessed the splicing and clinical impact of splice-site and exonic splicing enhancer (ESE) variants identified through the study of ~113,000 women of the BRIDGES cohort. A RAD51D minigene with exons 2–9 was constructed in splicing vector pSAD. Eleven BRIDGES splice-site variants (selected by MaxEntScan) were introduced into the minigene by site-directed mutagenesis and tested in MCF-7 cells. The 11 variants disrupted splicing, collectively generating 25 different aberrant transcripts. All variants but one produced negligible levels (<3.4%) of the full-length (FL) transcript. In addition, ESE elements of the alternative exon 3 were mapped by testing four overlapping exonic microdeletions (≥30-bp), revealing an ESE-rich interval (c.202_235del) with critical sequences for exon 3 recognition that might have been affected by germline variants. Next, 26 BRIDGES variants and 16 artificial exon 3 single-nucleotide substitutions were also assayed. Thirty variants impaired splicing with variable amounts (0–65.1%) of the FL transcript, although only c.202G > A demonstrated a complete aberrant splicing pattern without the FL transcript. On the other hand, c.214T > C increased efficiency of exon 3 recognition, so only the FL transcript was detected (100%). In conclusion, 41 RAD51D spliceogenic variants (28 of which were from the BRIDGES cohort) were identified by minigene assays. We show that minigene-based mapping of ESEs is a powerful approach for identifying ESE hotspots and ESE-disrupting variants. Finally, we have classified nine variants as likely pathogenic according to ACMG/AMP-based guidelines, highlighting the complex relationship between splicing alterations and variant interpretation.

show abstract

Section: Discussionmentioning

confidence: 66%

RAD51D Aberrant Splicing in Breast Cancer: Identification of Splicing Regulatory Elements and Minigene-Based Evaluation of 53 DNA Variants

Bueno-Martínez

Sanoguera-Miralles

Valenzuela-Palomo

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…BARD1 has been included in multi-gene panels since it was regarded as a potential cancer-predisposing gene [39], despite the lack of robust risk estimates. The identification of BARD1 PV carriers should be taken with caution, as inherited PVs in moderate-to low-penetrance genes may not necessarily be responsible for all the cancer diagnoses in a family.…”

Section: Discussionmentioning

confidence: 99%

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

Rofes

Valle

Torres-Esquius

et al. 2021

Genes

View full text Add to dashboard Cite

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.

show abstract

“…Depending on the population studied, between 5% and 40% of HBC and HBOC cancer syndromes families have not been accounted for by PVs in BRCA1 and BRCA2 [ 5 , 31 , 32 , 33 , 34 ]. Although the wide range in proportion of BRCA -negative families has been attributed to different criteria used to define cancer families, a consistent feature among these reports is that HBC syndrome families are more likely BRCA -negative than HBOC syndrome families ( Figure 1 a,b) [ 12 , 35 ].…”

Section: Methods Applied In the Identification Of Hbc And/or Hboc Syndrome Predisposing Gene Candidatesmentioning

confidence: 99%

“…Since the discovery of BRCA1 and BRCA2 , 12 new cancer predisposing genes have been proposed to play a role in BRCA -negative HBC/HBOC cancer syndrome families ( Table S1 ). These genes were identified using a candidate gene approach based on the knowledge that BRCA1 and BRCA2 proteins function in the repair of double stranded DNA breaks by homologous recombination (HR) (reviewed in [ 5 , 31 , 34 , 49 ]). As examples, ATM [ 50 ], BARD1 [ 31 , 51 , 52 ], BRIP1 [ 53 ], CHEK2 (whereby a genetic linkage analysis was used in combination with a candidate gene approach) [ 45 ], PALB2 [ 54 ], RAD51C [ 55 ], and RAD51D [ 56 ] were selected as plausible candidates because they either directly interact with BRCA1 or BRCA2 or are involved at some level in the HR DNA repair pathway [ 34 ].…”

Section: Methods Applied In the Identification Of Hbc And/or Hboc Syndrome Predisposing Gene Candidatesmentioning

confidence: 99%

The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families

Fierheller

Alenezi

Tonin

2021

Cancers

Self Cite

View full text Add to dashboard Cite

The French Canadian population of the province of Quebec has been recognized for its contribution to research in medical genetics, especially in defining the role of heritable pathogenic variants in cancer predisposing genes. Multiple carriers of a limited number of pathogenic variants in BRCA1 and BRCA2, the major risk genes for hereditary breast and/or ovarian cancer syndrome families, have been identified in French Canadians, which is in stark contrast to the array of over 2000 different pathogenic variants reported in each of these genes in other populations. As not all such cancer syndrome families are explained by BRCA1 and BRCA2, newly proposed gene candidates identified in other populations have been investigated for their role in conferring risk in French Canadian cancer families. For example, multiple carriers of distinct variants were identified in PALB2 and RAD51D. The unique genetic architecture of French Canadians has been attributed to shared ancestry due to common ancestors of early settlers of this population with origins mainly from France. In this review, we discuss the merits of genetically characterizing cancer predisposing genes in French Canadians of Quebec. We focused on genes that have been implicated in hereditary breast and/or ovarian cancer syndrome families as they have been the most thoroughly characterized cancer syndromes in this population. We describe how genetic analyses of French Canadians have facilitated: (i) the classification of variants in BRCA1 and BRCA2; (ii) the identification and classification of variants in newly proposed breast and/or ovarian cancer predisposing genes; and (iii) the identification of a new breast cancer predisposing gene candidate, RECQL. The genetic architecture of French Canadians provides a unique opportunity to evaluate new candidate cancer predisposing genes regardless of the population in which they were identified.

show abstract

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

Cited by 31 publications

References 163 publications

RAD51D Aberrant Splicing in Breast Cancer: Identification of Splicing Regulatory Elements and Minigene-Based Evaluation of 53 DNA Variants

RAD51D Aberrant Splicing in Breast Cancer: Identification of Splicing Regulatory Elements and Minigene-Based Evaluation of 53 DNA Variants

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

The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families

Contact Info

Product

Resources

About