Abstract
BackgroundBRM (Brahma homologue) is well known for its critical role in tumor suppression and cancer development. Genetic variations in the promoter region of BRM have been suggested to be associated with loss of BRM expression and lung cancer risk. To the authors’ knowledge, no study on the role of BRM genetic polymorphisms in hepatocellular carcinoma (HCC) risk has been performed.Methodology/Principal FindingsIn two independent case-control studies containing 796 HCC cases and 806 cancer-free individuals, we genotyped two putative functional insertion/deletion (indel) polymorphisms [BRM-1321 (rs3832613) and BRM-741 (rs34480940)] within promoter region of BRM in Chinese populations using a PCR-based method. Real-time RT-PCR analysis was used to explore the genotype-phenotype correlation between these polymorphisms and BRM expression in both tissue samples and HCC cell lines. Logistic regression analysis showed that compared to BRM-1321del/del genotype, the ins/del and ins/ins variant genotypes had an increased HCC risk [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.19–1.82; adjusted OR = 2.55, 95% CI = 1.75–3.72, respectively]. No significant association between BRM-741 and HCC incidence was observed. However, stratification analysis revealed a significant association between ins/ins genotype of BRM-741 and increased HCC susceptibility in smokers (adjusted OR = 2.07, 95% CI = 1.33–3.22). Quantitative PCR analyses demonstrated that the genotypes of BRM-1321 and the corresponding haplotypes were significantly correlated with BRM expression in vivo. Compared with ins/ins genotype, subjects carrying ins/del and del/del genotype had 2.30 and 4.99 fold higher BRM expression in HCC tissue samples, respectively. Similar trends were observed in western blot analysis at protein level.Conclusions/SignificanceOur findings suggest that BRM promoter polymorphism (BRM-1321) could regulate BRM expression and may serve as a potential marker for genetic susceptibility to HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver and its mortality rate is the third highest among the most common cancers [1]
By analyzing two indel polymorphisms within the promoter region of BRM in two independent case control studies, we find that the genotypes of the BRM-1321, not BRM-741, can influence hepatocellular carcinoma (HCC) incidence in Chinese populations
Functional assays reveal a significant genotype-phenotype correlation that the risk genotypes of BRM-1321 conferred lower BRM expression in vivo. These findings suggest that BRM promoter polymorphisms could regulate BRM expression and may serve as potential markers for genetic susceptibility to HCC
Summary
Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver and its mortality rate is the third highest among the most common cancers [1]. Epidemiological and clinical studies have demonstrated that the major risk factors for HCC include alcoholism, hepatitis B virus (HBV) and hepatitis C (HCV), aflatoxin, liver cirrhosis [3,4]. As the important carcinogen for HCC, HBV infection has become a significant public health problem in China [5]. Accumulated evidences from molecular genetics indicate that individual’s genetic and epigenetic factors are involved in their susceptibility to HCC [3]. To date, the molecular carcinogenic mechanism of HCC is still not fully elucidated. To the authors’ knowledge, no study on the role of BRM genetic polymorphisms in hepatocellular carcinoma (HCC) risk has been performed
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