Potentially functional variants of MAP3K14 in the NF-κB signaling pathway genes predict survival of HBV-related hepatocellular carcinoma patients

Qiongguang Huang; Yingchun Liu; Moqin Qiu; Qiuling Lin; Xueyan Wei; Zihan Zhou; Xiumei Liang; Runwei Li; Weiyi Chen; Xianguo Zhou; Hongping Yu

doi:10.3389/fonc.2022.990160

Potentially functional variants of MAP3K14 in the NF-κB signaling pathway genes predict survival of HBV-related hepatocellular carcinoma patients

Front Oncol. 2022 Sep 2:12:990160. doi: 10.3389/fonc.2022.990160. eCollection 2022.

Authors

Qiongguang Huang¹, Yingchun Liu², Moqin Qiu³, Qiuling Lin⁴, Xueyan Wei¹, Zihan Zhou⁵, Xiumei Liang⁶, Runwei Li⁷, Weiyi Chen¹, Xianguo Zhou², Hongping Yu^{1

2

8

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Affiliations

¹ School of Public Health, Guangxi Medical University, Nanning, China.
² Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, China.
³ Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital, Nanning, China.
⁴ Department of Clinical Research, Guangxi Medical University Cancer Hospital, Nanning, China.
⁵ Department of Cancer Prevention and Control, Guangxi Medical University Cancer Hospital, Nanning, China.
⁶ Department of Disease Process Management, Guangxi Medical University Cancer Hospital, Nanning, China.
⁷ Department of Occupational and Environmental Health, Indiana University, Bloomington, IN, United States.
⁸ Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, China.
⁹ Key Cultivated Laboratory of Cancer Molecular Medicine, Health Commission of Guangxi Zhuang Autonomous Region, Nanning, China.

Abstract

Background: The NF-κB signaling pathway plays an important role in associating inflammation with tumor development and progression. However, few studies have reported that roles of genetic variants of the NF-κB signaling pathway genes in survival of patients with HBV-related hepatocellular carcinoma (HBV-HCC), especially with regards to potentially functional SNPs.

Methods: We used multivariate Cox proportional hazards regression to evaluate associations between 2,060 single nucleotide polymorphisms (SNPs) in 20 NF-κB signaling pathway genes and survival of 866 HBV-HCC patients, which were randomly split (1:1) into discovery and validation datasets. Expression quantitative trait loci (eQTL) analysis was conducted to identify associations between survival-associated SNPs and mRNA expression of corresponding genes. Furthermore, online database was used to assess mRNA expression of corresponding genes and survival. Finally, receiver operating characteristic (ROC) curves were used to assess the prediction accuracy of models integrating both clinical and genetic variables on HCC survival.

Results: A total of 6 SNPs in MAP3K14 remained significantly associated with OS of HBV-HCC patients (P<0.05, BFDP<0.8). Further eQTL analysis demonstrated that significant correlations between the rs2074292 (G>A) A allele was associated with higher mRNA expression levels of MAP3K14 (P=0.044) in normal liver tissue, which was associated with worse survival of HBV-HCC patients. In the additive model, after adjusting for age, sex, smoking status, drinking status, AFP level, cirrhosis, embolus and BCLC stage, the combined dataset showed that HBV-HCC patients carrying the rs2074292 AA and GA genotypes (HR=1.71, 95%CI= 1.29-2.27, P=0.000) (HR=1.40, 95%CI=1.10-1.77, P=0.005) have worse OS than GG genotype, respectively. The addition of risk genotypes to the prediction models increased the AUC significantly from 71.15% to 73.11% (P=0.012) and from 72.55% to 74.21% (P=0.010) for 1-year and 3-year OS, respectively.

Conclusion: Our study indicated that MAP3K14 rs2074292 A allele may be a potential predictor of HBV-HCC survival, likely regulating MAP3K14 mRNA expression.

Keywords: MAP3K14; hepatocellular carcinoma; overall survival; single nucleotide polymorphism; variant.