WTAP Gene Variants Confer Hepatoblastoma Susceptibility: A Seven-Center Case-Control Study

Zhen-Jian Zhuo; Rui-Xi Hua; Zhen Chen; Jinhong Zhu; Mi Wang; Zhonghua Yang; Jiao Zhang; Yong Li; Li Li; Suhong Li; Yijuan Xin; Huimin Xia; Jing He

doi:10.1016/j.omto.2020.06.007

WTAP Gene Variants Confer Hepatoblastoma Susceptibility: A Seven-Center Case-Control Study

Mol Ther Oncolytics. 2020 Jun 9:18:118-125. doi: 10.1016/j.omto.2020.06.007. eCollection 2020 Sep 25.

Authors

Zhen-Jian Zhuo¹, Rui-Xi Hua^{1

2}, Zhen Chen³, Jinhong Zhu^{1

4}, Mi Wang¹, Zhonghua Yang⁵, Jiao Zhang⁶, Yong Li⁷, Li Li⁸, Suhong Li⁹, Yijuan Xin¹⁰, Huimin Xia¹, Jing He¹

Affiliations

¹ Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China.
² Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
³ Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing 100020, China.
⁴ Department of Clinical Laboratory, Biobank, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, China.
⁵ Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
⁶ Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
⁷ Department of Pediatric Surgery, Hunan Children's Hospital, Changsha, Hunan 410004, China.
⁸ Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Institute of Pediatrics Research, Yunnan Medical Center for Pediatric Diseases, Kunming Children's Hospital, Kunming, Yunnan 650228, China.
⁹ Department of Pathology, Children Hospital and Women Health Center of Shanxi, Taiyuan, Shannxi 030013, China.
¹⁰ Clinical Laboratory Medicine Center of PLA, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi 710032, China.

Abstract

Hepatoblastoma is a rare disease, and its etiology remains to be revealed. Wilms tumor suppressor-1-associated protein (WTAP) plays a critical role in tumorigenesis. However, whether single nucleotide polymorphisms (SNPs) of the WTAP gene predispose to hepatoblastoma risk awaits to be investigated. With the use of the TaqMan assay, we evaluated the genotype frequencies of three WTAP SNPs (rs7766006 G > T, rs9457712 G > A, and rs1853259 A > G) in Chinese children with 313 hepatoblastoma patients and 1,446 controls. Among these three SNPs, only the rs7766006 T allele exhibited a significant association with hepatoblastoma risk (GT versus GG: adjusted odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.53-0.92, p = 0.009; GT/TT versus GG: adjusted OR = 0.73, 95% CI = 0.57-0.95, p = 0.017). Combined analysis indicated that subjects with two risk genotypes showed significantly higher hepatoblastoma risk, compared to individuals without a risk genotype (adjusted OR = 1.38, 95% CI = 1.02-1.88, p = 0.037). The stratified analysis revealed that the rs1853259 GG genotype, the rs7766006 GT/TT genotype, and two risk genotypes modified hepatoblastoma risk in certain subgroups. The significant results were validated by haplotype analyses and false-positive report probability analyses. Furthermore, the expression quantitative trait locus analysis indicated that rs7766006 T was associated with decreased expression of WTAP mRNA. Collectively, our results suggest that WTAP SNPs may be genetic modifiers for the development of hepatoblastoma.

Keywords: WTAP; hepatoblastoma; m6A; polymorphism; susceptibility.