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    • A number of lines of evidence

    2018-10-23

    A number of lines of evidence has suggested BARD1 as a tumor suppressor (Irminger-Finger and Jefford, 2006; Irminger-Finger et al., 2016). BRCA1-BARD1 heterodimer plays a crucial role in homologous repair in response to DNA damage (Stark et al., 2004). The knockout of Bard1 is lethal in mouse (McCarthy et al., 2003). The study of Bard1 knockout mice demonstrated that BARD1 is indispensible to maintain cell viability and genetic stability (McCarthy et al., 2003). Conditional knockout Bard1 in mammary epithelia phosphatidylinositol 4-kinase induced the development of breast cancer, which mimics the human breast cancer phenotype observed in individuals, harboring BRCA1 mutation (Shakya et al., 2008). Mechanistic studies indicated that the BARD1-BRCA1 heterodimer is also implicated in ubiquitin dependent protein degradation as an E3 ubiquitin ligase (Hashizume et al., 2001). Mutations that impaired the E3 ubiquitin ligase activity of the heterodimer predispose to breast and ovarian cancer (Brzovic et al., 2001; Hashizume et al., 2001; Ruffner et al., 2001). Moreover, some non-synonymous polymorphisms (e.g., cys557Ser, Arg378Ser, Val507Met, and Pro24Ser) in the BARD1gene have been also frequently investigated for their association with cancer susceptibility, and studies mainly involved breast cancer (Morris et al., 2006; Onay et al., 2006; Stacey et al., 2006; Vahteristo et al., 2006; Guenard et al., 2009; Ding et al., 2011; Sun et al., 2012), neuroblastoma (Capasso et al., 2009, 2013), and cervical cancer (Zhou et al., 2009). Nonetheless, the associations between these BARD1 SNPs and cancer susceptibility have been often paradoxical. Some studies supported the associations (Huo et al., 2007), while others had opposite results (Liu et al., 2015). The factors that contribute to the inconsistency are, but not limited to differences in genotyping methods, experiment designs (hospital-based design or population-based design), different populations and ethnicities, as well as sample size of studies. Therefore, it is critical that all association studies consider external validity issues and candidly state the populations to which the results can be applied. Several meta-analyses were undertaken to reevaluate such associations (Ding et al., 2011; Liu et al., 2015). Ding et al. reported a lack of association between BARD1 Cys557Ser polymorphism and breast cancer risk in a pooled analysis comprising 11,870 cases and 7687 controls in 2011 (Ding et al., 2011). Liu et al. collected 10 case-control studies in 2015 (Liu et al., 2015). They found that BARD1 Val507Met and Pro24Ser polymorphisms were associated with decreased cancer risk independently, but not BARD1 Arg378Ser (Liu et al., 2015). A number of limitations of this study should be noted. First, owing to the extremely low incidence of nephroblastoma, the sample size of this case-control was relatively small. Consequently, statistic power of this study was compromised (statistical power no more than 0.307 for significant findings). The significant findings might be chance observations (FPRP values larger than 0.2 at the prior probability level of 0.1). Second, we concentrated on only three BARD1 SNPs. BARD1 gene is highly polymorphic, harboring 4941 SNPs as a minimum (http://www.ncbi.nlm.nih.gov.eleen.top/projects/SNP). Other SNPs that potentially affect the expression and function of BARD1 should be investigated in the future. Third, we only included Southern Chinese Children in this study. These findings cannot be generalized from one ethnicity to another before validation study. Fourth, in this retrospective study, some important information (e.g., parental exposures) was not available. Due to differences in genetic backgrounds and environmental exposures among the different ethnicities, these findings should be cross-validated with different populations. Notwithstanding these limitations, our finding did suggest that the rs7585356 G>A polymorphism may confer genetic susceptibility to nephroblastoma. The studied SNPs collectively may increase the risk of nephroblastoma. Moreover, these SNPs appear to be related to the clinical stages of this disease. Well-designed, large, multi-center studies are warranted to strengthen these findings.