A germline <i>BARD1</i> mutation in a patient with Ewing Sarcoma: Implications for familial testing and counseling

Venier, Rosemarie E.; Maurer, Lisa M.; Kessler, E; Ranganathan, Sarangarajan; McGough, Richard L.; Weiß, Kurt; Malek, Marcus M.; Meade, Julia; Tersak, Jean M.; Bailey, Kelly M.

doi:10.1002/pbc.27824

Cited by 15 publications

(16 citation statements)

References 9 publications

(11 reference statements)

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“…Although it is hypothesized that BARD1-EWS recruits CstF-50 and alters mRNA processing, the function of this interaction still needs to be further elucidated. Recently, the first germline variation in the BARD1 gene was identified in a patient with relapsed Ewing sarcoma [ 130 ]. A frameshift mutation in BARD1 c.176_177AG; p.E59Afs*8 occurred in the RING domain.…”

Section: Bard1 In Non-breast and Non-gynecological Cancersmentioning

confidence: 99%

The Effects of Genetic and Epigenetic Alterations of BARD1 on the Development of Non-Breast and Non-Gynecological Cancers

Watters

Seltzer

MacKenzie

et al. 2020

Genes

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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.

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Section: Bard1 In Non-breast and Non-gynecological Cancersmentioning

confidence: 99%

The Effects of Genetic and Epigenetic Alterations of BARD1 on the Development of Non-Breast and Non-Gynecological Cancers

Watters

Seltzer

MacKenzie

et al. 2020

Genes

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“…Pathogenic germline BARD1 mutations provide a moderate risk for heritable breast cancer and have also been reported in pediatric patients diagnosed with high risk neuroblastoma [24][25][26]. We previously reported our discovery of a pathogenic germline BARD1 mutation in a patient with Ewing sarcoma [12]. To better understand the frequency of germline BARD1 mutations in pediatric malignancies, we investigated the presence of germline BARD1 mutations in two pediatric oncology sequencing databases: PEDS-MiONCOseq and St. Jude Cloud PeCan (…”

Section: The Landscape Of Germline Bard1 Mutations In Pediatric Oncolmentioning

confidence: 99%

“…Germline DNA damage repair mutations are reported in >10% of patients with Ewing sarcoma [11]. We have previously reported a patient with Ewing sarcoma who harbors a pathogenic germline BARD1 mutation that results in a frameshift that introduces a premature stop codon within the RING domain of BARD1 [12]. This patient was enrolled in our IRB-approved Musculoskeletal Oncology Biobank and Tumor Registry (MOTR) and viable tumor was banked at the time of relapse.…”

Section: Psarc318: a Patient-derived Ewing Sarcoma Cell Linementioning

confidence: 99%

“…In addition to the DNA damage repair defects imparted by EWS-FLI1 itself, germline mutations in DNA damage repair genes, such as APC, BRCA1, FANCC, and RAD51, have been identified in greater than 10% of patients with Ewing sarcoma [11]. We recently contributed to this growing body of literature by reporting our discovery of a paternally inherited germline frameshift mutation in the RING domain of BARD1 (BRCA1-associated RING domain protein 1) in a patient with Ewing sarcoma [12]. BARD1, a tumor suppressor, is an obligatory binding partner of BRCA1.…”

Section: Introductionmentioning

confidence: 99%

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PARP inhibition in Ewing sarcoma: impact of germline DNA damage repair defects and activation of immunoregulatory pathways

Maurer¹,

Venier

Mukherjee³

et al. 2020

Preprint

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Ewing sarcoma, an oncofusion-driven primary bone tumor, can occur in the setting of various germline mutations in DNA damage repair pathway genes. We recently reported our discovery of a germline mutation in the DNA damage repair protein BARD1 (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the poly(ADP-ribose) polymerase (PARP) protein and plays a critical role in DNA damage response pathways including homologous recombination. PARP inhibitors (PARPi) are effective against Ewing sarcoma cells in vitro, though have demonstrated limited success in clinical trials to date. In order to assess the impact of BARD1 loss on Ewing sarcoma sensitivity to PARP inhibitor therapy, we generated the novel PSaRC318 patient-derived Ewing tumor cell from our patient with a germline BARD1 mutation and then analyzed the response of these cells to PARPi. We demonstrate that PSaRC318 cells are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that loss of BARD1 enhances PARPi sensitivity. In certain malignancies, DNA damage can activate the IRF1 (interferon response factor 1) immunoregulatory pathway, and the activation of this pathway can drive immunosuppression through upregulation of the immune checkpoint protein PD-L1. In order to determine the ability of PARPi to alter Ewing tumor immunoregulation, we evaluated whether PARPi results in upregulation of the IRF1-PDL1 pathway. Indeed, we now demonstrate that PARPi leads to increased PD-L1 expression in Ewing sarcoma. Together, these data thus far suggest that while Ewing tumors harboring germline mutations in DNA damage repair proteins may in respond to PARPi in vitro, in vivo benefit of PARPi may only be demonstrated when counteracting the immunosuppressive effects of DNA damage by concurrently targeting immune checkpoint proteins.

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“…The expression of BARD1 isoforms was widely studied in several adult type malignancies, such as colorectal, lung, and gynaecological cancers, whereas its role in pediatric tumours is yet to be discovered [ 12 , 13 , 14 ]. The best-analyzed is neuroblastoma, but only limited data on BARD1 is available for Wilms’ tumour, case studies in Ewing sarcoma, and osteosarcoma or does not exist as in case of GCT or RMS [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

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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A germline BARD1 mutation in a patient with Ewing Sarcoma: Implications for familial testing and counseling

Cited by 15 publications

References 9 publications

The Effects of Genetic and Epigenetic Alterations of BARD1 on the Development of Non-Breast and Non-Gynecological Cancers

The Effects of Genetic and Epigenetic Alterations of BARD1 on the Development of Non-Breast and Non-Gynecological Cancers

PARP inhibition in Ewing sarcoma: impact of germline DNA damage repair defects and activation of immunoregulatory pathways

Expression of BARD1 β Isoform in Selected Pediatric Tumors

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