Functional polymorphisms of the lncRNA H19 promoter region contribute to the cancer risk and clinical outcomes in advanced colorectal cancer

Wenyan Qin; Xiaodong Wang; Yilin Wang; Yalun Li; Qiuchen Chen; Xiaoyun Hu; Zhikun Wu; Pengfei Zhao; Shanqiong Li; Haishan Zhao; Weifan Yao; Jian Ding; Minjie Wei; Huizhe Wu

doi:10.1186/s12935-019-0895-x

Functional polymorphisms of the lncRNA H19 promoter region contribute to the cancer risk and clinical outcomes in advanced colorectal cancer

Cancer Cell Int. 2019 Aug 20:19:215. doi: 10.1186/s12935-019-0895-x. eCollection 2019.

Authors

Wenyan Qin^#¹, Xiaodong Wang^#¹, Yilin Wang¹, Yalun Li², Qiuchen Chen¹, Xiaoyun Hu¹, Zhikun Wu¹, Pengfei Zhao¹, Shanqiong Li¹, Haishan Zhao¹, Weifan Yao¹, Jian Ding^{1

3}, Minjie Wei¹, Huizhe Wu¹

Affiliations

¹ 1Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122 People's Republic of China.
² 2Department of Anorectal Surgery, First Hospital of China Medical University, Shenyang, 110001 People's Republic of China.
³ 3Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China.

^# Contributed equally.

Abstract

Background: The long non-coding RNA H19 plays critical roles in cancer occurrence, development, and progression. The present study is for the first time to evaluate the association of genetic variations in the H19 promoter region with advanced colorectal cancer (CRC) susceptibility, environmental factors, and clinical outcomes.

Methods: 16 single-nucleotide polymorphisms (SNPs) were identified in the H19 gene promoter by DNA sequencing, and 3 SNPs among which including rs4930101, rs11042170, and rs2735970 further expanded samples with 572 advanced CRC patients and 555 healthy controls.

Results: We found that harboring SNP [rs4930101 (P = 0.009), rs2735970 (P = 0.003), and rs11042170 (P = 0.003)] or carrying more than one combined risk genotypes significantly increased the risk for CRC [P < 0.0001, adjusted OR (95% CI) 6.48 (2.97-14.15)]. In the correlation analysis with environmental factors, rs2735970 and gender, combined risk genotypes (> 1 vs. ≤ 1) and family history of cancer demonstrated significant interactions. Furthermore, a remarkably worse clinical outcome was found in combined risk genotypes (> 1 vs. ≤ 1), especially in CRC patients with body weight ≥ 61 kg, smoking, and first-degree family history of cancer (Log-rank test: P = 0.006, P = 0.018, and P = 0.013, respectively). More importantly, the multivariate Cox regression analyses further verified that combined risk genotypes > 1 showed a prognostic risk factor for CRC patients with body weight ≥ 61 kg (P = 0.002), smoking (P = 0.008), and family history of cancer (P = 0.006). In addition, MDR analysis consistently revealed that the combination of selected SNPs and nine known risk factors showed a better prediction prognosis and represented the best model to predict advanced CRC prognosis.

Conclusion: 3 SNPs of rs4930101, rs11042170, and rs27359703 among 16 identified SNPs of H19 gene remarkably increased CRC risk. Furthermore, the combined risk genotypes had a significant impact on environmental factors and clinical outcomes in the advanced CRC patients with body weight ≥ 61 kg, ever-smoking, and first-degree family history of cancer. These data suggest that H19 promoter SNPs, especially these combined SNPs might be more potentially functional biomarkers in the prediction of advanced CRC risk and prognosis.

Keywords: Colorectal cancer; Genetic polymorphisms; H19; Prognosis; Susceptibility.