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

Watters, Andrea; Seltzer, Emily S.; MacKenzie, Danny; Young, Melody W.; Muratori, Jonathan; Hussein, Rama; Sodoma, Andrej M.; To, Julie T.; Singh, Manrose; Zhang, Dong

doi:10.3390/genes11070829

Cited by 16 publications

(16 citation statements)

References 146 publications

(257 reference statements)

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“…Our study also proposes BARD1 as a prognostic gene in stage IV ovarian cancer. BARD1 , BRCA1‐associated RING domain 1, acts as a tumor suppressor gene and its interaction with BRCA1 is essential for the tumor suppression activity of BRCA1 34 . In our study, the AA and AG genotypes of rs16852804 (G>A) in BARD1 were associated with shorter OS.…”

Section: Discussionsupporting

confidence: 48%

Genome‐wide association studies of survival in 1520 cancer patients treated with bevacizumab‐containing regimens

Quintanilha

Wang

Sibley

et al. 2021

Intl Journal of Cancer

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Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta‐analysis of genome‐wide association studies (GWAS) was conducted in 1,520 patients from Phase III trials (CALGB 80303, 40503, 80405 and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and single nucleotide polymorphisms (SNPs) associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause‐specific Cox model was used to test the SNP‐OS association in both arms combined (prognostic), and the effect of SNPs‐bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta‐analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (P = 1.02 × 10−7, hazard ratio [HR] = 1.57, 95% confidence interval [CI] 1.33‐1.86), as well as in TCGA (P = .0219, HR = 1.58, 95% CI 1.07‐2.35). In the GWAS meta‐analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (P = 1.40 × 10−5, HR = 1.51, 95% CI 1.25‐1.82) as well as in TCGA (P = 1.39 × 10−4, HR = 3.09, 95% CI 1.73‐5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the nonbevacizumab arm (P = 1.43 × 10−5). The largest GWAS meta‐analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival.

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Section: Discussionsupporting

confidence: 48%

Genome‐wide association studies of survival in 1520 cancer patients treated with bevacizumab‐containing regimens

Quintanilha

Wang

Sibley

et al. 2021

Intl Journal of Cancer

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“…Several lines of evidence from genome-wide association studies (GWAS) in neuroblastomas have identified predisposing SNPs in BARD1 (BRCA1-associated RING domain1), which is a potent interacting protein of BRCA1. As the BRCA1-BRAD1 complex has been implicated in initiating DNA end resection and promoting RAD51 loading in HR [ 56 , 57 ], it remains unclear what the direct roles of BRCA1 and the other mediators of DDR are in neuroblastoma pathogenesis. Importantly, BRCA1-deficient tumors are critically dependent on abrogation of p53 function in mice and humans, suggesting that the combination of DDR deficiency and loss-of-function p53 is highly susceptible for tumorigenesis.…”

Section: “Accelerating” the Cell Cycle To Induce Catastrophic Cell Deathmentioning

confidence: 99%

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Ando

Nakagawara

2021

Biomolecules

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Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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“…Regulation of alternative splicing process by H3K36me3 reduced BARD1 expression with subsequent suppression of ATM/ATR signaling that regulates hESC differentiation [ 47 ]. Another report revealed that in patients with hepatocellular carcinoma (HCC) that ended by the cirrhotic liver, the BARD1 gene showed significant hypomethylation (13.3%) in comparison to normal controls BARD1 hypomethylation was suggested as a predictive biomarker for predisposing to aggressive disease in HBV-negative patients [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

BARD1 mystery: tumor suppressors are cancer susceptibility genes

et al. 2022

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The full-length BRCA1-associated RING domain 1 (BARD1) gene encodes a 777-aa protein. BARD1 displays a dual role in cancer development and progression as it acts as a tumor suppressor and an oncogene. Structurally, BARD1 has homologous domains to BRCA1 that aid their heterodimer interaction to inhibit the progression of different cancers such as breast and ovarian cancers following the BRCA1-dependant pathway. In addition, BARD1 was shown to be involved in other pathways that are involved in tumor suppression (BRCA1-independent pathway) such as the TP53-dependent apoptotic signaling pathway. However, there are abundant BARD1 isoforms exist that are different from the full-length BARD1 due to nonsense and frameshift mutations, or deletions were found to be associated with susceptibility to various cancers including neuroblastoma, lung, breast, and cervical cancers. This article reviews the spectrum of BARD1 full-length genes and its different isoforms and their anticipated associated risk. Additionally, the study also highlights the role of BARD1 as an oncogene in breast cancer patients and its potential uses as a prognostic/diagnostic biomarker and as a therapeutic target for cancer susceptibility testing and treatment.

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

Cited by 16 publications

References 146 publications

Genome‐wide association studies of survival in 1520 cancer patients treated with bevacizumab‐containing regimens

Genome‐wide association studies of survival in 1520 cancer patients treated with bevacizumab‐containing regimens

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

BARD1 mystery: tumor suppressors are cancer susceptibility genes

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