BARD1 in Cancer

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 December 2020) | Viewed by 38995

Special Issue Editors


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Guest Editor
Centre for Cell Therapy and Regenerative Medicine, University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia
Interests: BARD1; BRCA1; BARD1 splicing; BARD1 isoforms; breast cancer; ovarian cancer; lung cancer; biomarkers; treatment targets

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Guest Editor
1. Department of Pathology, Dunedin School of Medicine, University of Otago, 60 Hanover Street, Dunedin 9016, New Zealand
2. Department of Biology and Medical Genetics, Medical University of Gdansk, Debinki 1 St., 80-210 Gdansk, Poland
Interests: genetic testing; epigenetic; hereditary cancer; breast and ovarian cancer

Special Issue Information

Dear Colleagues,

BARD1 is the main binding partner of BRCA1, and it is required for its stability and tumor-suppressor functions. While upregulation of alternatively spliced BARD1 isoforms is a common finding in many epithelial cancers, germline mutations are a relatively rare finding, with conflicting reports on their role in the predisposition to cancer. Thus, understanding the cellular functions of BARD1 and its role as both a potential prognostic marker and a possible risk factor in cancer predisposition is of the highest importance.

In this Special Issue, we welcome reviews, short reports, and original articles covering many aspects of BARD1 biology. These include but are not limited to mutation testing, alternative splicing findings, and the functional relationship between networks representing co-expression of well-known BARD1 isoforms and their association with a disease.

We look forward to your contributions.

Dr. Irmgard Irminger-Finger
Dr. Magda Ratajska
Guest Editors

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Keywords

  • BARD1 mutations
  • BARD1 splicing
  • BARD1 DNA repair functions

Published Papers (9 papers)

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Research

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13 pages, 2465 KiB  
Article
BARD1 Autoantibody Blood Test for Early Detection of Ovarian Cancer
by Maxim Pilyugin, Magdalena Ratajska, Maciej Stukan, Nicole Concin, Robert Zeillinger and Irmgard Irminger-Finger
Genes 2021, 12(7), 969; https://doi.org/10.3390/genes12070969 - 25 Jun 2021
Cited by 4 | Viewed by 2806
Abstract
Background: Ovarian cancer (OC) is the most lethal gynaecological cancer. It is often diagnosed at an advanced stage with poor chances for successful treatment. An accurate blood test for the early detection of OC could reduce the mortality of this disease. Methods: Autoantibody [...] Read more.
Background: Ovarian cancer (OC) is the most lethal gynaecological cancer. It is often diagnosed at an advanced stage with poor chances for successful treatment. An accurate blood test for the early detection of OC could reduce the mortality of this disease. Methods: Autoantibody reactivity to 20 epitopes of BARD1 and concentration of cancer antigen 125 (CA125) were assessed in 480 serum samples of OC patients and healthy controls. Autoantibody reactivity and CA125 were also tested for 261 plasma samples of OC with or without mutations in BRCA1/2, BARD1, or other predisposing genes, and healthy controls. Lasso statistic regression was applied to measurements to develop an algorithm for discrimination between OC and controls. Findings and interpretation: Measurement of autoantibody binding to a number of BARD1 epitopes combined with CA125 could distinguish OC from healthy controls with high accuracy. This BARD1-CA125 test was more accurate than measurements of BARD1 autoantibody or CA125 alone for all OC stages and menopausal status. A BARD1-CA125-based test is expected to work equally well for average-risk women and high-risk women with hereditary breast and ovarian cancer syndrome (HBOC). Although these results are promising, further data on well-characterised clinical samples shall be used to confirm the potential of the BARD1-CA125 test for ovarian cancer screening. Full article
(This article belongs to the Special Issue BARD1 in Cancer)
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14 pages, 1832 KiB  
Article
Expression of BARD1 β Isoform in Selected Pediatric Tumors
by Anna Jasiak, Natalia Krawczyńska, Mariola Iliszko, Katarzyna Czarnota, Kamil Buczkowski, Joanna Stefanowicz, Elżbieta Adamkiewicz-Drożyńska, Grzegorz Cichosz and Ewa Iżycka-Świeszewska
Genes 2021, 12(2), 168; https://doi.org/10.3390/genes12020168 - 26 Jan 2021
Cited by 1 | Viewed by 2096
Abstract
Currently, many new possible biomarkers and mechanisms are being searched and tested to analyse pathobiology of pediatric tumours for the development of new treatments. One such candidate molecular factor is BARD1 (BRCA1 Associated RING Domain 1)—a tumour-suppressing gene involved in cell cycle control [...] Read more.
Currently, many new possible biomarkers and mechanisms are being searched and tested to analyse pathobiology of pediatric tumours for the development of new treatments. One such candidate molecular factor is BARD1 (BRCA1 Associated RING Domain 1)—a tumour-suppressing gene involved in cell cycle control and genome stability, engaged in several types of adult-type tumours. The data on BARD1 significance in childhood cancer is limited. This study determines the expression level of BARD1 and its isoform beta (β) in three different histogenetic groups of pediatric cancer—neuroblastic tumours, and for the first time in chosen germ cell tumours (GCT), and rhabdomyosarcoma (RMS), using the qPCR method. We found higher expression of beta isoform in tumour compared to healthy tissue with no such changes concerning BARD1 full-length. Additionally, differences in expression of BARD1 β between histological types of neuroblastic tumours were observed, with higher levels in ganglioneuroblastoma and ganglioneuroma. Furthermore, a higher expression of BARD1 β characterized yolk sac tumours (GCT type) and RMS when comparing with non-neoplastic tissue. These tumours also showed a high expression of the TERT (Telomerase Reverse Transcriptase) gene. In two RMS cases we found deep decrease of BARD1 β in post-chemotherapy samples. This work supports the oncogenicity of the beta isoform in pediatric tumours, as well as demonstrates the differences in its expression depending on the histological type of neoplasm, and the level of maturation in neuroblastic tumours. Full article
(This article belongs to the Special Issue BARD1 in Cancer)
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11 pages, 362 KiB  
Article
BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort
by 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
Genes 2021, 12(2), 150; https://doi.org/10.3390/genes12020150 - 23 Jan 2021
Cited by 10 | Viewed by 4903
Abstract
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, [...] Read more.
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. Full article
(This article belongs to the Special Issue BARD1 in Cancer)
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18 pages, 1187 KiB  
Article
Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations
by Malwina Suszynska and Piotr Kozlowski
Genes 2020, 11(7), 798; https://doi.org/10.3390/genes11070798 - 15 Jul 2020
Cited by 15 | Viewed by 4488
Abstract
Over the last two decades, numerous BARD1 mutations/pathogenic variants (PVs) have been found in patients with breast cancer (BC) and ovarian cancer (OC). However, their role in BC and OC susceptibility remains controversial, and strong evidence-based guidelines for carriers are not yet available. [...] Read more.
Over the last two decades, numerous BARD1 mutations/pathogenic variants (PVs) have been found in patients with breast cancer (BC) and ovarian cancer (OC). However, their role in BC and OC susceptibility remains controversial, and strong evidence-based guidelines for carriers are not yet available. Herein, we present a comprehensive catalog of BARD1 PVs identified in large cumulative cohorts of ~48,700 BC and ~20,800 OC cases (retrieved from 123 studies examining the whole coding sequence of BARD1). Using these resources, we compared the frequency of BARD1 PVs in the cases and ~134,100 controls from the gnomAD database and estimated the effect of the BARD1 PVs on BC and OC risks. The analysis revealed that BARD1 is a BC moderate-risk gene (odds ratio (OR) = 2.90, 95% CIs:2.25–3.75, p < 0.0001) but not an OC risk gene (OR = 1.36, 95% CIs:0.87–2.11, p = 0.1733). In addition, the BARD1 mutational spectrum outlined in this study allowed us to determine recurrent PVs and evaluate the variant-specific risk for the most frequent PVs. In conclusion, these precise estimates improve the understanding of the role of BARD1 PVs in BC and OC predisposition and support the need for BARD1 diagnostic testing in BC patients. Full article
(This article belongs to the Special Issue BARD1 in Cancer)
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Review

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12 pages, 532 KiB  
Review
BARD1 and Breast Cancer: The Possibility of Creating Screening Tests and New Preventive and Therapeutic Pathways for Predisposed Women
by Marcin Śniadecki, Michał Brzeziński, Katarzyna Darecka, Dagmara Klasa-Mazurkiewicz, Patryk Poniewierza, Marta Krzeszowiec, Natalia Kmieć and Dariusz Wydra
Genes 2020, 11(11), 1251; https://doi.org/10.3390/genes11111251 - 24 Oct 2020
Cited by 13 | Viewed by 3630
Abstract
Current oncological developments are based on improved understanding of genetics, and especially the discovery of genes whose alterations affect cell functions with consequences for the whole body. Our work is focused on the one of these genes, BRCA1-associated RING domain protein 1 [...] Read more.
Current oncological developments are based on improved understanding of genetics, and especially the discovery of genes whose alterations affect cell functions with consequences for the whole body. Our work is focused on the one of these genes, BRCA1-associated RING domain protein 1 (BARD1), and its oncogenic role in breast cancer. Most importantly, the study points to new avenues in the treatment and prevention of the most frequent female cancer based on BARD1 research. The BARD1 and BRCA1 (BReast CAncer type 1) proteins have similar structures and functions, and they combine to form the new molecule BARD1-BRCA1 heterodimer. The BARD1-BRCA1 complex is involved in genetic stabilization at the cellular level. It allows to mark abnormal DNA fragments by attaching ubiquitin to them. In addition, it blocks (by ubiquitination of RNA polymerase II) the transcription of damaged DNA. Ubiquitination, as well as stabilizing chromatin, or regulating the number of centrosomes, confirms the protective cooperation of BARD1 and BRCA1 in the stabilization of the genome. The overexpression of the oncogenic isoforms BARD1β and BARD1δ permit cancer development. The introduction of routine tests, for instance, to identify the presence of the BARD1β isoform, would make it possible to detect patients at high risk of developing cancer. On the other hand, introducing BARD1δ isoform blocking therapy, which would reduce estrogen sensitivity, may be a new line of cancer therapy with potential to modulate responses to existing treatments. It is possible that the BARD 1 gene offers new hope for improving breast cancer therapy. Full article
(This article belongs to the Special Issue BARD1 in Cancer)
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24 pages, 1156 KiB  
Review
Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers
by Wejdan M. Alenezi, Caitlin T. Fierheller, Neil Recio and Patricia N. Tonin
Genes 2020, 11(8), 856; https://doi.org/10.3390/genes11080856 - 27 Jul 2020
Cited by 31 | Viewed by 8503
Abstract
Soon after the discovery of BRCA1 and BRCA2 over 20 years ago, it became apparent that not all hereditary breast and/or ovarian cancer syndrome families were explained by germline variants in these cancer predisposing genes, suggesting that other such genes have yet to [...] Read more.
Soon after the discovery of BRCA1 and BRCA2 over 20 years ago, it became apparent that not all hereditary breast and/or ovarian cancer syndrome families were explained by germline variants in these cancer predisposing genes, suggesting that other such genes have yet to be discovered. BRCA1-associated ring domain (BARD1), a direct interacting partner of BRCA1, was one of the earliest candidates investigated. Sequencing analyses revealed that potentially pathogenic BARD1 variants likely conferred a low–moderate risk to hereditary breast cancer, but this association is inconsistent. Here, we review studies of BARD1 as a cancer predisposing gene and illustrate the challenge of discovering additional cancer risk genes for hereditary breast and/or ovarian cancer. We selected peer reviewed research articles that focused on three themes: (i) sequence analyses of BARD1 to identify potentially pathogenic germline variants in adult hereditary cancer syndromes; (ii) biological assays of BARD1 variants to assess their effect on protein function; and (iii) association studies of BARD1 variants in family-based and case-control study groups to assess cancer risk. In conclusion, BARD1 is likely to be a low–moderate penetrance breast cancer risk gene. Full article
(This article belongs to the Special Issue BARD1 in Cancer)
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13 pages, 1128 KiB  
Review
The Function of BARD1 in Centrosome Regulation in Cooperation with BRCA1/OLA1/RACK1
by Kei Otsuka, Yuki Yoshino, Huicheng Qi and Natsuko Chiba
Genes 2020, 11(8), 842; https://doi.org/10.3390/genes11080842 - 24 Jul 2020
Cited by 10 | Viewed by 4317
Abstract
Breast cancer gene 1 (BRCA1)-associated RING domain protein 1 (BARD1) forms a heterodimer with BRCA1, a tumor suppressor associated with hereditary breast and ovarian cancer. BRCA1/BARD1 functions in multiple cellular processes including DNA repair and centrosome regulation. Centrosomes are the major microtubule-organizing centers [...] Read more.
Breast cancer gene 1 (BRCA1)-associated RING domain protein 1 (BARD1) forms a heterodimer with BRCA1, a tumor suppressor associated with hereditary breast and ovarian cancer. BRCA1/BARD1 functions in multiple cellular processes including DNA repair and centrosome regulation. Centrosomes are the major microtubule-organizing centers in animal cells and are critical for the formation of a bipolar mitotic spindle. BRCA1 and BARD1 localize to the centrosome during the cell cycle, and the BRCA1/BARD1 dimer ubiquitinates centrosomal proteins to regulate centrosome function. We identified Obg-like ATPase 1 (OLA1) and receptor for activated C kinase (RACK1) as BRCA1/BARD1-interating proteins that bind to BARD1 and BRCA1 and localize the centrosomes during the cell cycle. Cancer-derived variants of BRCA1, BARD1, OLA1, and RACK1 failed to interact, and aberrant expression of these proteins caused centrosome amplification due to centriole overduplication only in mammary tissue-derived cells. In S-G2 phase, the number of centrioles was higher in mammary tissue-derived cells than in cells from other tissues, suggesting their involvement in tissue-specific carcinogenesis by BRCA1 and BARD1 germline mutations. We described the function of BARD1 in centrosome regulation in cooperation with BRCA1/OLA1/RACK1, as well as the effect of their dysfunction on carcinogenesis. Full article
(This article belongs to the Special Issue BARD1 in Cancer)
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25 pages, 1061 KiB  
Review
The Effects of Genetic and Epigenetic Alterations of BARD1 on the Development of Non-Breast and Non-Gynecological Cancers
by Andrea K. Watters, Emily S. Seltzer, Danny MacKenzie, Jr., Melody Young, Jonathan Muratori, Rama Hussein, Andrej M. Sodoma, Julie To, Manrose Singh and Dong Zhang
Genes 2020, 11(7), 829; https://doi.org/10.3390/genes11070829 - 21 Jul 2020
Cited by 13 | Viewed by 4191
Abstract
Breast Cancer 1 (BRCA1) gene is a well-characterized tumor suppressor gene, mutations of which are primarily found in women with breast and ovarian cancers. BRCA1-associated RING domain 1 (BARD1) gene has also been identified as an important tumor suppressor [...] Read more.
Breast Cancer 1 (BRCA1) gene is a well-characterized tumor suppressor gene, mutations of which are primarily found in women with breast and ovarian cancers. BRCA1-associated RING domain 1 (BARD1) gene has also been identified as an important tumor suppressor gene in breast, ovarian, and uterine cancers. Underscoring the functional significance of the BRCA1 and BARD1 interactions, prevalent mutations in the BRCA1 gene are found in its RING domain, through which it binds the RING domain of BARD1. BARD1-BRCA1 heterodimer plays a crucial role in a variety of DNA damage response (DDR) pathways, including DNA damage checkpoint and homologous recombination (HR). However, many mutations in both BARD1 and BRCA1 also exist in other domains that significantly affect their biological functions. Intriguingly, recent genome-wide studies have identified various single nucleotide polymorphisms (SNPs), genetic alterations, and epigenetic modifications in or near the BARD1 gene that manifested profound effects on tumorigenesis in a variety of non-breast and non-gynecological cancers. In this review, we will briefly discuss the molecular functions of BARD1, including its BRCA1-dependent as well as BRCA1-independent functions. We will then focus on evaluating the common BARD1 related SNPs as well as genetic and epigenetic changes that occur in the non-BRCA1-dominant cancers, including neuroblastoma, lung, and gastrointestinal cancers. Furthermore, the pro- and anti-tumorigenic functions of different SNPs and BARD1 variants will also be discussed. Full article
(This article belongs to the Special Issue BARD1 in Cancer)
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10 pages, 1230 KiB  
Brief Report
Differential Expression of BARD1 Isoforms in Melanoma
by Lorissa I. McDougall, Ryan M. Powell, Magdalena Ratajska, Chi F. Lynch-Sutherland, Sultana Mehbuba Hossain, George A. R. Wiggins, Agnieszka Harazin-Lechowska, Bożena Cybulska-Stopa, Jyoti Motwani, Erin C. Macaulay, Glen Reid, Logan C. Walker, Janusz Ryś and Michael R. Eccles
Genes 2021, 12(2), 320; https://doi.org/10.3390/genes12020320 - 23 Feb 2021
Cited by 2 | Viewed by 3046
Abstract
Melanoma comprises <5% of cutaneous malignancies, yet it causes a significant proportion of skin cancer-related deaths worldwide. While new therapies for melanoma have been developed, not all patients respond well. Thus, further research is required to better predict patient outcomes. Using long-range nanopore [...] Read more.
Melanoma comprises <5% of cutaneous malignancies, yet it causes a significant proportion of skin cancer-related deaths worldwide. While new therapies for melanoma have been developed, not all patients respond well. Thus, further research is required to better predict patient outcomes. Using long-range nanopore sequencing, RT-qPCR, and RNA sequencing analyses, we examined the transcription of BARD1 splice isoforms in melanoma cell lines and patient tissue samples. Seventy-six BARD1 mRNA variants were identified in total, with several previously characterised isoforms (γ, φ, δ, ε, and η) contributing to a large proportion of the expressed transcripts. In addition, we identified four novel splice events, namely, Δ(E3_E9), ▼(i8), IVS10+131▼46, and IVS10▼176, occurring in various combinations in multiple transcripts. We found that short-read RNA-Seq analyses were limited in their ability to predict isoforms containing multiple non-contiguous splicing events, as compared to long-range nanopore sequencing. These studies suggest that further investigations into the functional significance of the identified BARD1 splice variants in melanoma are warranted. Full article
(This article belongs to the Special Issue BARD1 in Cancer)
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