A missense polymorphism in ATF6 gene is associated with susceptibility to hepatocellular carcinoma probably by altering ATF6 level. Issue 1 (21st December 2013)

• Record Type: Journal Article
• Authors: Wu, Xiaopan; Xin, Zhenhui; Zhang, Wei; Zheng, Sujun; Wu, Jia; Chen, Kangmei; Wang, Huifen; Zhu, Xilin; Li, Zhuo; Duan, Zhongping; Li, Hui; Liu, Ying
• Is Part Of: International journal of cancer. Volume 135:Issue 1(2014:Jul. 01)
• Page Start: 61
• Page End: 68
• Publication Date: 2013-12-21
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28649
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Accumulated evidences indicate that single nucleotide polymorphisms (SNP) are associated with risk of hepatocellular carcinoma (HCC). Activating transcription factor 6 (ATF6) is an important modulator of the unfolded protein response (UPR), which is regarded to be involved in carcinogenesis. So we speculate that SNPs in <italic>ATF6</italic> may be associated with susceptibility to HCC. We carried out a two‐stage association study in three independent case–control groups in a total of 1, 082 chronic hepatitis B (CHB) patients and 816 hepatitis B virus (HBV) related HCC patients in Han Chinese. Four SNPs which can represent all potential functional SNPs with MAF > 0.1 recorded in HapMap database in <italic>ATF6</italic> gene were genotyped using TaqMan methods. Functional analyses were conducted to verify the biological significances of the associated SNP. We identified a missense SNP (rs2070150) was significantly associated with susceptibility to HCC (<italic>p</italic> = 0.008, 0.001 and 0.007 in Beijing_302, Beijing_You'an and Guangxi samples, respectively). This SNP was further validated in four independent groups of major HBV outcomes, indicating it may associate exclusively to HCC. <italic>ATF6</italic> mRNA expression was significantly decreased as the disease progressed (<italic>p</italic> <0.001). Functional analyses show that the protective allele of rs2070150 could significantly increase the expression levels of <italic>ATF6</italic> mRNA, as well as ATF6 regulated genes such as <italic>GRP78</italic>, <italic>XBP1</italic> and <italic>CHOP</italic>. These findings indicate that a common missense SNP in <italic>ATF6</italic> may contribute to susceptibility of HCC functionally.</p> </abstract>