Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels

Abstract

The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single‐nucleotide polymorphisms in a large case‐control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at HLA‐DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79‐0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04‐1.31, P = .008) and with high‐grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70‐0.87, P = 7.1 × 10−6; rs2844511: OR 1.13, 95% CI 1.01‐1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75‐0.91, P = 6.9 × 10−5; rs2844511: OR 1.14, 95% CI 1.04‐1.26, P = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low‐grade dysplasia (OR 1.26, 95% CI 1.04‐1.54, P = .019). In case‐only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA‐DQA1, suggesting extensive co‐regulation. All three genes were upregulated in HPV16‐positive samples. In stratified analyses, rs9272117 was associated with HLA‐DQA1 levels, specifically in HPV‐positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA‐DQA1. Altogether, our results support 6p21.32‐33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of HLA‐DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.

Association of genomic variants at PAX8 and PBX2 with cervical cancer risk

“…The German Cervigen Study has been described previously 13 . 4061 samples were used for the present case‐control analysis, after exclusion of patients with known non‐European ancestry.…”

“…Median age at diagnosis was 44 years (range 17‐94 years) for patients with invasive cervical cancer and 31 years (range 16‐79 years) for patients with cervical dysplasia, compared to a median age at recruitment of 32 years (range 18‐86 years) for healthy female controls. The sample and histology distribution per centre have been described previously 13 . 5 mL peripheral venous EDTA blood was taken for genomic DNA extraction, and methanol‐fixed cervical tissue smears were obtained from a smaller cohort of independent healthy participants without invasive cancer.…”

“…Example cluster plots are shown in Supplemental Figure 1. SNPtype genotyping results had already been obtained in this series for two previously tested signals at the HLA locus, rs9272117 ( HLA‐DQA1 ) and rs2844511 ( MICA/ HCP5 ) 13 so that these genotypes were additionally used with rs2856437 in a multivariate analysis.…”

“…There is an increased familial relative risk for cervical cancer, 3‐5 and array heritability estimates are in the similar range as for colon or ovarian cancer 6,7 . Despite this evidence for hereditary genetic factors, only one genomic locus, HLA on chromosome 6, has been consistently associated with cervical cancer risk so far 8‐13 . The HLA region modulates the host response to viral infection, 14,15 and it has been proposed that risk variants at this locus regulate genes that are important for cervical tumour immune evasion.…”

Long non-coding RNA signatures as predictors of prognosis in thyroid cancer: a narrative review

“…HCP5, an oncogenic lncRNA, has an important role in various types of cancers, including colon cancer (56,57), cervical cancer (58,59), and TC (60). HCP5 upregulation has been identified using next-generation sequencing technology in FTC (23).…”