Association of genomic variants at the Human Leukocyte Antigen locus with cervical cancer risk, HPV status, and gene expression
Menée en Allemagne auprès de 1 405 femmes présentant des lésions cervicales, 1 042 femmes atteintes d'un cancer du col de l'utérus et de 1 556 témoins (âge médian au diagnostic : 31-44 ans), cette étude analyse l'association entre 2 polymorphismes à simple nucléotide de gènes du système HLA et le risque de développer la maladie, en fonction du statut HPV
The 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 = 0.036; rs2844511: OR 1.17, 95% CI 1.04-1.31, P = 0.008) and with high-grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70-0.87, P = 7.1 x 10−6; rs2844511: OR 1.13, 95% CI 1.01-1.26, P = 0.035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75-0.91, P = 6.9 x 10−5; rs2844511: OR 1.14, 95% CI 1.04-1.26, P = 0.005). 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 = 0.019). In case-only analyses, rs2844511 tended to predict HPV status (P = 0.044) and rs9272117 tended to associate with HPV16 (P = 0.022). Gene expression studies in cervical tissue showed a significant correlation in the transcript levels of MICA, HCP5, and HLA-DQA1, suggesting transcriptional co-regulation. All three genes were upregulated in HPV16-positive tissue. In stratified analyses, rs9272117 was associated with HLA-DQA1 levels, specifically in HPV-positive tissue, 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.