Antagonizing functions of BARD1 and its alternatively spliced variant BARD1δ in telomere stability

Pilyugin, Maxim; André, Pierre Alain; Ratajska, Magdalena; Kuźniacka, Alina; Limon, Janusz; Tournier, Benjamin B.; Colas, Julien; Laurent, GJ; Irminger-Finger, Irmgard

doi:10.18632/oncotarget.14068

Cited by 9 publications

(12 citation statements)

References 68 publications

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“…In the present study, we described an individual being a compound heterozygous for BARD1 , with an in-frame deletion in exon 4, c.1075_1095del (p.Leu359_Pro365del), and a silent mutation c.1977A>G, reside in trans position ( Figures S1 and S2 ). Both alterations lead to missplicing and overexpression of alternative isoforms, named gamma and eta , and consequently, to significant telomere instability [ 42 ]. Taking into account a positive family history for OC, potential actionability of those variants cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients

Koczkowska

Krawczyńska

Stukan

et al. 2018

Cancers

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Constitutional loss-of-function pathogenic variants in the tumor suppressor genes BRCA1 and BRCA2 are widely associated with an elevated risk of ovarian cancer (OC). As only ~15% of OC individuals carry the BRCA1/2 pathogenic variants, the identification of other potential OC-susceptibility genes is of great clinical importance. Here, we established the prevalence and spectrum of the germline pathogenic variants in the BRCA1/2 and 23 other cancer-related genes in a large Polish population of 333 unselected OC cases. Approximately 21% of cases (71/333) carried the BRCA1/2 pathogenic or likely pathogenic variants, with c.5266dup (p.Gln1756Profs*74) and c.3700_3704del (p.Val1234Glnfs*8) being the most prevalent. Additionally, ~6% of women (20/333) were carriers of the pathogenic or likely pathogenic variants in other cancer-related genes, with NBN and CHEK2 reported as the most frequently mutated, accounting for 1.8% (6/333) and 1.2% (4/333) of cases, respectively. We also found ten pathogenic or likely pathogenic variants in other genes: 1/333 in APC, 1/333 in ATM, 2/333 in BLM, 1/333 in BRIP1, 1/333 in MRE11A, 2/333 in PALB2, 1/333 in RAD50, and 1/333 in RAD51C, accounting for 50% of all detected variants in moderate- and low-penetrant genes. Our findings confirmed the presence of the additional OC-associated genes in the Polish population that may improve the personalized risk assessment of these individuals.

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Section: Discussionmentioning

confidence: 99%

Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients

Koczkowska

Krawczyńska

Stukan

et al. 2018

Cancers

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“…To note, BARD1δ dominant negative of FL BARD1 is temporally and spatially regulated by estrogen signaling in human invasive cytotrophoblasts cells of early pregnancy [ 81 ]. Recently, Maxim Pilyugin et al described BARD1δ antagonizes chromosome and telomere protection function of BARD1-BRCA1 heterodimer by binding molecules that confer chromosome integrity [ 84 ]. It is likely that BARD1δ confers genomic instability and acquired oncogenic property in absence of cell cycle control, due to p53 deficiency and of chromosome integrity.…”

Section: Biological Functions Of Bard1 As Oncogenementioning

confidence: 99%

Dualistic Role of BARD1 in Cancer

Cimmino

Formicola

Capasso

2017

Genes

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BRCA1 Associated RING Domain 1 (BARD1) encodes a protein which interacts with the N-terminal region of BRCA1 in vivo and in vitro. The full length (FL) BARD1 mRNA includes 11 exons and encodes a protein comprising of six domains (N-terminal RING-finger domain, three Ankyrin repeats and two C-terminal BRCT domains) with different functions. Emerging data suggest that BARD1 can have both tumor-suppressor gene and oncogene functions in tumor initiation and progression. Indeed, whereas FL BARD1 protein acts as tumor-suppressor with and without BRCA1 interactions, aberrant splice variants of BARD1 have been detected in various cancers and have been shown to play an oncogenic role. Further evidence for a dualistic role came with the identification of BARD1 as a neuroblastoma predisposition gene in our genome wide association study which has demonstrated that single nucleotide polymorphisms in BARD1 can correlate with risk or can protect against cancer based on their association with the expression of FL and splice variants of BARD1. This review is an overview of how BARD1 functions in tumorigenesis with opposite effects in various types of cancer.

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“…Here, we describe the analysis of BARD1 β in three types of childhood cancers: neuroblastoma, germ cell tumours, and rhabdomyosarcoma. The previous data suggest that a high level of BARD1 β is associated with an adverse prognosis in different cancer types [ 5 , 12 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of BARD1 β Isoform in Selected Pediatric Tumors

Jasiak

Krawczyńska

Iliszko

et al. 2021

Genes

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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.

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Antagonizing functions of BARD1 and its alternatively spliced variant BARD1δ in telomere stability

Cited by 9 publications

References 68 publications

Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients

Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients

Dualistic Role of BARD1 in Cancer

Expression of BARD1 β Isoform in Selected Pediatric Tumors

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