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.

译文

:乳腺癌1(BRCA1)基因是特征明确的抑癌基因,其突变主要在患有乳腺癌和卵巢癌的女性中发现。 BRCA1相关的RING域1(BARD1)基因也已被确定为乳腺癌,卵巢癌和子宫癌的重要抑癌基因。突出BRCA1和BARD1相互作用的功能重要性,发现BRCA1基因在其RING域中普遍存在突变,通过该突变与BARD1的RING域结合。 BARD1-BRCA1异二聚体在包括DNA损伤检查点和同源重组(HR)在内的各种DNA损伤反应(DDR)途径中起着至关重要的作用。但是,BARD1和BRCA1中的许多突变也存在于其他域中,这些突变会显着影响其生物学功能。有趣的是,最近的全基因组研究已经确定了BARD1基因内或附近的各种单核苷酸多态性(SNP),遗传变异和表观遗传修饰,这些变异对各种非乳腺癌和非妇科癌症的肿瘤发生均产生了深远的影响。在这篇综述中,我们将简要讨论BARD1的分子功能,包括其依赖于BRCA1的功能以及不依赖于BRCA1的功能。然后,我们将专注于评估常见的BARD1相关SNP以及在非BRCA1占主导地位的癌症(包括神经母细胞瘤,肺癌和胃肠道癌症)中发生的遗传和表观遗传学变化。此外,还将讨论不同SNP和BARD1变体的促肿瘤和抗肿瘤功能。

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