Interaction between susceptibility loci in cGAS-STING pathway, MHC gene and HPV infection on the risk of cervical precancerous lesions in Chinese population.

Di Xiao,Zihao Wen,Baohuan Zhang,Weihuang Huang,Chengli Zeng,Meiling Ou,Chenfei Wu,Chuican Huang,Na Zhang,Man Wang,Shiqi Huang,Xiangcai Wei,Chunxia Jing,Yang Liu,Xingguang Ye,Congcong Guo,Jiankun Zang,Guang Yang,Zixing Zhou

doi:10.18632/oncotarget.12399

Abstract

Human papillomavirus (HPV) infection is a definite risk factor for cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The cGAS-STING pathway in innate immunity plays an important role in protecting against HPV infection. Chen et al. described that the rs2516448 SNP in the MHC locus may affect susceptibility to cervical cancer, a finding that we attempted to replicate in a Chinese population. To investigate the effects of cGAS, STING and MHC polymorphisms on susceptibility to cervical precancerous lesions, 9 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene-gene and gene-environment interactions were also evaluated. We found a significantly decreased risk of cervical precancerous lesions for the GG genotype of rs311678 in the cGAS gene (ORadjusted = 0.40, 95% CI: 0.16−0.98). Moreover, MDR analysis identified a significant three-locus interaction model, involving HPV infection, age at menarche and rs311678 in cGAS. Additionally, a significant antagonistic interaction between HPV infection and rs311678 was found on an additive scale. In conclusion, our results indicate that the rs311678 polymorphism in the cGAS gene confers genetic susceptibility to cervical precancerous lesions. Moreover, the three-way gene-environment interactions further demonstrate that the rs311678 polymorphism in cGAS can significantly decrease the risk of HPV infection and the elder at menarche.

Highlights

Cervical cancer is the third most common cancer among women, with approximately 530,000 new cases annually worldwide [1]
We found that individuals with the GG genotype in cGAMP synthase (cGAS) rs311678 had a 60% decreased risk of developing cervical precancerous lesions (ORadjusted = 0.40, 95% confidence intervals (CIs) = 0.16–0.98, P = 0.045) compared with those with the AA wild-type, while the other 8 SNPs were not observed to be relevant to the risk of cervical precancerous lesions
To investigate whether SNPs in these molecules affected the occurrence of cervical precancerous lesions, our study comprehensively evaluated the associations between variants of the cGAS-stimulator of interferon genes (STING) pathway, the major histocompatibility complex (MHC) and cervical precancerous lesions

Summary

Introduction

Cervical cancer is the third most common cancer among women, with approximately 530,000 new cases annually worldwide [1]. With more than half a million new cases and 275,000 deaths per year, cervical cancer continues to constitute a major public health problem and affects young women in developing countries [2, 3]. Cervical cancer develops through a multistep process, with three cervical intraepithelial neoplasia grades, 1 to 3 (CIN1-3) [4]. It will take several years, even decades, from pre-cancer to invasive cervical cancer, which offers us many opportunities for intervention. Molecular and epidemiologic studies have shown that persistent infection with high-risk HPV plays a role in the development of both cervical cancer and cervical precancerous lesions [6,7,8]. HPV is an essential factor for the transformation of cervical epithelial cells, it is not sufficient, and a variety of environmental and host factors influence the development of cervical cancer

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Results

Conclusion