Jiang Tao, Du Fangzhi, Qin Na, Lu Qun, Dai Juncheng, Shen Hongbing, Hu Zhibin
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China.
J Gastroenterol Hepatol. 2017 Nov;32(11):1887-1894. doi: 10.1111/jgh.13790.
Although several variants located at coding and non-coding regions were evaluated by previous studies, the evidence for associations between variants located in DNase I-hypersensitive sites (DHSs) and hepatocellular carcinoma (HCC) risk was still limited. Recent advances using ENCODE data indicated that genetic variants in DHSs played an important role in carcinogenesis. Therefore, systematically investigating the associations between regulatory variants in DHSs and HCC risk should be put on the agenda.
We conducted a case-control design (1538 HCC cases vs 1465 normal controls) to evaluate the effects on HCC for the variants located at the uniform DNase I hypersensitive sites sequencing peaks in a Chinese population.
We found two novel single nucleotide polymorphisms rs12309362 (odds ratio = 0.64, P = 5.61 × 10 ) and rs9970827 (odds ratio = 0.73, P = 7.23 × 10 ) significantly associated with decreased risk of HCC. Conditional analysis proved that both of them independently contributed to the susceptibility of HCC. Expression quantitative trait loci analysis found that A allele of rs12309362 was significantly associated with an elevated expression of phosphatase phosphoglycerate mutase 5 in liver tissues. In addition, gene-based analysis indicated that CEBPB (P = 1 × 10 ) was associated with the risk of HCC, and the expression of CEBPB was significantly lower in 50 The Cancer Genome Atlas HCC tumor tissues compared with matched normal tissues.
Our results indicated that rs12309362 (G > A), rs9970827 (A > G) in DHSs, and elevated expression of CEBPB were associated with a decreased risk of HCC. These results may contribute us to understand the function of regulatory DNA sequences in HCC development.
尽管先前的研究评估了位于编码区和非编码区的多个变异，但位于DNA酶I超敏位点（DHSs）的变异与肝细胞癌（HCC）风险之间关联的证据仍然有限。利用ENCODE数据的最新进展表明，DHSs中的遗传变异在致癌过程中起重要作用。因此，系统研究DHSs中的调控变异与HCC风险之间的关联应提上日程。
我们进行了一项病例对照研究（1538例HCC病例对1465例正常对照），以评估中国人群中位于统一DNA酶I超敏位点测序峰处的变异对HCC的影响。
我们发现两个新的单核苷酸多态性rs12309362（优势比=0.64，P=5.61×10 ）和rs9970827（优势比=0.73，P=7.23×10 ）与HCC风险降低显著相关。条件分析证明它们两者均独立影响HCC易感性。表达数量性状位点分析发现，rs12309362的A等位基因与肝组织中磷酸甘油酸变位酶5的表达升高显著相关。此外，基于基因的分析表明，CEBPB（P=1×10 ）与HCC风险相关，并且与配对的正常组织相比，在50个癌症基因组图谱HCC肿瘤组织中CEBPB的表达显著降低。
我们的结果表明，DHSs中的rs12309362（G>A）、rs9970827（A>G）以及CEBPB的表达升高与HCC风险降低相关。这些结果可能有助于我们了解调控DNA序列在HCC发生发展中的作用。
