宫颈癌是女性第四大常见癌症。全基因组关联研究 (GWAS) 提出了 6p21 号染色体上的 HLA 基因座存在宫颈癌易感性变异。为了证实这些发现并研究它们对宫颈组织和细胞系的功能影响，我们对宫颈癌 GWAS 的 9 个变异（rs17190106、rs535777、rs1056429、rs2763979、rs143954678、rs113937848、rs3117027、rs3130214 和 rs947）进行了基因分型。 7610）在德国一家医院该系列包括 1122 例浸润性宫颈癌、1408 例不典型增生和 1196 例健康对照。 rs17190106、rs1056429 和 rs143954678/rs113937848 与宫颈恶性肿瘤总体相关，而 rs17190106 和 rs535777 与浸润性癌症特异性相关（OR = 0.69，95% CI = 0.55-0.86，p = 0 .001) 或腺癌 (OR = 1.63, 95%CI = 1.17-2.27，p = 0.004）。我们测试了这些以及之前基因分型的 GWAS 变体 rs9272117，以了解 eQTL 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影响。最强的 eQTL 对是 rs9272117 和 HLA-DRB6 (p = 1.9x10E-5)、rs1056429 和 HLA-DRB5 (p = 2.5x10E-4)、rs535777 和 HLA-DRB1 (p = 2.7x10E-4)。我们还鉴定了 HPV 或 HPV16 样本中特异性上调（DDX39B、HCP5、HLA-B、LTB、NFKBIL1）或下调（HLA-C、HLA-DPB2）的转录本。相比之下，用促炎细胞因子 γ-IFN 处理宫颈上皮细胞会导致 HCP5、HLA-B、HLA-C、HLA-DQB1、HLA-DRB1、HLA-DRB6 的剂量依赖性诱导和 HSPA1L 的抑制。总而言之，这些结果确定了来自 MHC I 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，并且与 HPV（HCP5、HLA-B、HLA-C）和/或基因组宫颈癌风险变异相关。 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。© 2024 作者。 HLA：免疫反应遗传学，约翰·威利 (John Wiley) 出版

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.© 2024 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.