宫颈癌是女性中第四常见的癌症。全基因组关联研究(GWAS)提出了染色体6p21上HLA基因座的宫颈癌易感性变异。为了证实这些发现,并研究它们在宫颈组织和细胞系中的功能影响,我们对来自宫颈癌GWASs的9种变异(rs17190106,rs535777,rs1056429,rs2763979,rs143954678,rs113937848,rs3117027,rs3130214和rs9477610)进行了基因分型。1408发育不良,和1196个健康对照。rs17190106,rs1056429和rs143954678/rs113937848与宫颈恶性肿瘤相关,而rs17190106和rs535777与浸润性癌(OR=0.69,95%CI=0.55-0.86,p=0.001)或腺癌(OR=1.63,95CI=1.17-2.27,p=0.004)特异性相关,分别。我们测试了这些和一个以前基因分型的GWAS变异体,rs9272117,用于对280个宫颈上皮组织中HLA基因座的36个基因转录本的潜在eQTL效应。最强的eQTL对是rs9272117和HLA-DRB6(p=1.9x10E-5),rs1056429和HLA-DRB5(p=2.5x10E-4),和rs535777和HLA-DRB1(p=2.7x10E-4)。我们还鉴定了特异性上调的转录本(DDX39B,HCP5,HLA-B,LTB,NFKBIL1)或下调(HLA-C,HLA-DPB2)在HPV+或HPV16+样品中。相比之下,用促炎细胞因子γ-IFN处理宫颈上皮细胞导致HCP5,HLA-B,HLA-C,HLA-DQB1,HLA-DRB1,HLA-DRB6和HSPA1L的抑制。一起来看,这些结果鉴定了来自MHCI类和II类区域的相关基因,这些基因在宫颈上皮中具有炎症反应性,并与HPV(HCP5,HLA-B,HLA-C)和/或基因组宫颈癌风险变异(HLA-DRB1,HLA-DRB6)。因此,它们可能是HPV感染后癌前细胞免疫逃逸的重要贡献者。
Cervical cancer is the fourth most common cancer in females. Genome-wide association studies (GWASs) have proposed cervical cancer susceptibility variants at the HLA locus on chromosome 6p21. To corroborate these findings and investigate their functional impact in cervical tissues and cell lines, we genotyped nine variants from cervical cancer GWASs (rs17190106, rs535777, rs1056429, rs2763979, rs143954678, rs113937848, rs3117027, rs3130214, and rs9477610) in a German hospital-based series of 1122 invasive cervical cancers, 1408 dysplasias, and 1196 healthy controls. rs17190106, rs1056429 and rs143954678/rs113937848 associated with cervical malignancies overall, while rs17190106 and rs535777 associated specifically with invasive cancer (OR = 0.69, 95% CI = 0.55-0.86, p = 0.001) or adenocarcinomas (OR = 1.63, 95%CI = 1.17-2.27, p = 0.004), respectively. We tested these and one previously genotyped GWAS variant, rs9272117, for potential
eQTL effects on 36 gene transcripts at the HLA locus in 280 cervical epithelial tissues. The strongest
eQTL pairs were rs9272117 and HLA-DRB6 (p = 1.9x10E-5), rs1056429 and HLA-DRB5 (p = 2.5x10E-4), and rs535777 and HLA-DRB1 (p = 2.7x10E-4). We also identified transcripts that were specifically upregulated (DDX39B, HCP5, HLA-B, LTB, NFKBIL1) or downregulated (HLA-C, HLA-DPB2) in HPV+ or HPV16+ samples. In comparison, treating cervical epithelial cells with proinflammatory cytokine γ-IFN led to a dose-dependent induction of HCP5, HLA-B, HLA-C, HLA-DQB1, HLA-DRB1, HLA-DRB6, and repression of HSPA1L. Taken together, these results identify relevant genes from both the MHC class I and II regions that are inflammation-responsive in cervical epithelium and associate with HPV (HCP5, HLA-B, HLA-C) and/or with genomic cervical cancer risk variants (HLA-DRB1, HLA-DRB6). They may thus constitute important contributors to the immune escape of precancerous cells after HPV-infection.