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Dualistic Role of BARD1 in Cancer.

ABSTRACT: 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.

SUBMITTER: Cimmino F

PROVIDER: S-EPMC5748693 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Dualistic Role of BARD1 in Cancer.

Cimmino Flora F Formicola Daniela D Capasso Mario M

Genes 20171208 12

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 prot ...[more]

PMID: 29292755

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Project description:Human epidermal growth factor receptor 2 (HER2/ERBB2) factor is known to be implicated in many malignancies and the potential of it as a prognostic biomarker was reported years ago. Molecular subtypes of HER2/ERBB2 negative and positive with distinct clinical outcomes have been identified in recent years; however, it is still under investigation for bladder cancer. This study evaluates the biological and prognostic significance of RAD21, RAD50 and BARD1 (homologous recombination biomarkers) mRNA levels with ERBB2 low and high expression to explore their impact on bladder cancer patient survival and cancer aggressiveness. The expression of ERBB2, RAD21, RAD50 and BARD1 mRNA levels was assessed in The Cancer Genome Atlas (TCGA) bladder cancer dataset along with four validation cohorts. Outcome analysis was evaluated using disease-free survival (DFS) and overall survival (OS). Univariate and multivariate analysis were used to evaluate the relationship between RAD21, RAD50, BARD1 and ERBB2 expression and clinicopathological variables. A significant increase in mRNA expression levels of RAD21, RAD50 and BARD1 was noticed in ERBB2-low patients compared to ERBB2-high patients. This overexpression of the homologous recombination repair transcripts was associated with poor outcome in ERBB2-low tumors, not in ERBB2-high tumors. Furthermore, the combined expression of high RAD21/RAD50, high RAD21/BARD1 or high RAD50/BARD1 were significantly associated with worse DFS and a better outcome for those with low co-expression in the ERBB2-low cohort. High expression of either RAD21/RAD50 or RAD21/BARD1 in ERBB2-low cohort associated with higher chance of metastasis. In addition, gene expression of BARD1 alone or in combination with RAD50 acted as an independent prognostic factor for worst survival. The data presented in this study reveal a connection between RAD21, RAD50, BARD1 and ERBB2 and patient survival. Importantly, it provided novel findings and potential prognostic markers, particularly in ERBB2-low bladder cancer.

Project description:BackgroundMost, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.Methods and findingsThe Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents.ConclusionsOur findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.

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Dualistic Role of BARD1 in Cancer.

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Dualistic Role of BARD1 in Cancer.

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