Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus

Dan Chen,Ulf Gyllensten,Min Yu,Huibo Wang,Yang Sun,Shuhua Xu,Stefan Enroth,Lian Deng,Han Liu

doi:10.18632/oncotarget.9916

Abstract

Recent genome-wide association studies (GWASs) in subjects of European descent have identified associations between cervical cancer risk and three independent loci as well as multiple classical human leukocyte antigen (HLA) alleles at 6p21.3. To search for novel loci associated with development of cervical cancer, we performed a pooled analysis of data from two GWASs by imputing over 10 million genetic variants and 424 classical HLA alleles, for 1,553 intraepithelial neoplasia 3 (CIN3), 81 cervical cancer and 4,442 controls from the Swedish population. Notable findings were validated in an independent study of 961 patients (827 with CIN3 and 123 with cervical cancer) and 1,725 controls. Our data provided increased support for previously identified loci at 6p21.3 (rs9271898, P = 1.2 × 10−24; rs2516448, 1.1 × 10−15; and rs3130196, 2.3 × 10−9, respectively) and also confirmed associations with reported classical HLA alleles including HLA-B*07:02, -B*15:01, -DRB1*13:01, -DRB1*15:01, -DQA1*01:03, -DQB1*06:03 and -DQB1*06:02. In addition, we identified and subsequently replicated an independent signal at rs73730372 at 6p21.3 (odds ratio = 0.60, 95% confidence interval = 0.54–0.67, P = 3.0 × 10−19), which was found to be an expression quantitative trait locus (eQTL) of both HLA-DQA1 and HLA-DQB1. This is one of the strongest common genetic protective variants identified so far for CIN3. We also found HLA-C*07:02 to be associated with risk of CIN3. The present study provides new insights into pathogenesis of CIN3.

Highlights

Worldwide, cervical cancer is the fourth most common cancer in women [1]
To search for novel loci associated with development of cervical cancer, we performed a pooled analysis of data from two genome-wide association studies (GWASs) by imputing over 10 million genetic variants and 424 classical human leukocyte antigen (HLA) alleles, for 1,553 intraepithelial neoplasia 3 (CIN3), 81 cervical cancer and 4,442 controls from the Swedish population
After stringent quality control (QC), data from 1,634 cases (1,553 CIN3 and 81 cervical cancer) and 4,442 controls were available for 5,471,179 single-nucleotide polymorphism (SNP) with an overall call rate of 99.32%

Summary

Introduction

Persistent infection with carcinogenic human papillomavirus (HPV) strains is the main cause of cervical cancer and its precursor lesions, cervical intraepithelial neoplasia (CIN) [2]. More advanced lesions, designated CIN3, are considered to be the same as carcinoma in situ (CIS) or Stage 0 cervical cancer. Both population screening and a prophylactic vaccine are available, cervical cancer continues to be a major threat to female health globally. We recently performed the first genome-wide association study (GWAS) of cervical precancer (CIN3) in a Swedish population and confirmed previously reported associations with classical human leukocyte antigen (HLA) alleles, including HLA-B*07:02, -DRB1*13:01, -DRB1*15:01, -DQA1*01:03, -DQB1*06:03 and -DQB1*06:02. We identified three novel loci in the major histocompatibility complex (MHC) region at 6p21.3, rs9272143 between HLA-DRB1 and HLA-DQA1, rs2516448 adjacent to the MHC class I polypeptide-related sequence A gene (MICA) and rs3117027 at of HLA-DPB2, which acted independently of classical HLA alleles [3]

Methods

Results

Conclusion