Question

What other cancers or disease (if any) are BARD1 gene carriers predisposed to? please explain?

Answer 1

BARD1; BRCA1 associated RING domain 1 is a gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Genes encoding proteins that interact with BRCA1 and BRCA2 in different DNA damage response and tumor suppressor processes are among the candidate BC and/or OC susceptibility genes. One such gene that has been intensively studied is BRCA1-associated RING domain 1 (BARD1) , because the BARD1 protein shares both structural and functional similarities with BRCA1 and because the interaction between BARD1 and BRCA1 plays an important role in maintaining the stability and manifestation of the tumor suppressor function of BRCA1.

In humans, the BARD1 gene spans a region of ~80 kb on the long arm of chromosome 2 (2q34-35) and comprises 11 exons. The gene encodes a protein of 777 amino acids that contains one N-terminal RING-finger domain, two C-terminal tandem BRCT domains (homologous to corresponding domains in BRCA1), and three Ankyrin (ANK) repeat domains. BARD1 may act as a tumor suppressor in the BRCA1-dependent pathways, which is associated with specific BRCA1/BARD1 heterodimer formation via N-terminal RING-finger domains. The BRCA1/BARD1 heterodimer demonstrates ubiquitin ligase activity, which functions in DNA damage response pathways, cell cycle regulation, and chromatin structural and hormone signaling modulation. Because BARD1 may interact with other molecules implicated in genome integrity, a BRCA1-independent tumor suppressor functions for BARD1 have also been suggested. Examples include the interaction between BARD1 and p53, which stabilizes p53, facilitates p53 phosphorylation, and induces p53 apoptotic activity in response to DNA damage.

The hitherto reported BARD1 mutation screening studies of familial and unselected BC and/or OC cases has led to the identification of numerous BARD1 sequence variants. Additionally, BARD1 common variants have been associated with an aggressive subset of human neuroblastomas , lung cancer and colon cancer. BARD1 mutations identified in BC cases include deleterious and potentially deleterious mutations that lead to premature termination of translation, disruption of protein structure/function, or alternative splicing. Some of these mutations have been shown to cosegregate in families with cancer.