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

Abstract

Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta‐analysis, 2q14.1 (PAX8) and 6p21.32 (PBX2) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case‐control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at PAX8 and rs2856437 at PBX2, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74‐0.91, P = 2.4 × 10−4; rs2856437: OR 1.52, 95% CI 1.14‐2.02, P = .004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462: OR 0.80, 95% CI 0.68‐0.94, P = .006; rs2856437: OR 1.56, 95% CI 1.03‐2.36, P = .036) and with high‐grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70‐0.90, P = 1.9 × 10−4; rs2856437: OR 1.58, 95% CI 1.15‐2.17, P = .005). A combined analysis of high‐grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73‐0.91, P = 2.4 × 10−4; rs2856437: OR 1.57, 95% CI 1.18‐2.10, P = .002). No association was detected for rs2856437 with low‐grade dysplasia, while rs10175462 showed weak evidence of association (P = .05). RNA analyses in cervical samples revealed that PAX8 transcripts were upregulated in HPV‐positive lesions (P = .008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA PAX8‐AS1 (P < .001). Taken together, our results extend the evidence for a link between genomic risk variants at the HLA region (PBX2) with cervical disease and support PAX8 as the first consistent non‐HLA cervical cancer susceptibility locus.

Genomic Risk Factors for Cervical Cancer

“…This study not only confirmed previously known variants at the HLA locus but also identified a novel variant at genome-wide significance on 2q13 (rs10175462) near the PAX8 gene encoding the transcription factor Paired box 8 [68]. This signal replicated in the UK biobank and in the FinnGen biobank [121] as well as in a German case-control study [146] and in the transethnic meta-analysis GWAS from the Estonian Biobank, the FinnGen study, the UK Biobank and Biobank Japan (rs4849177, [122]). Two weakly correlated variants, rs4848320 and rs1110839, had been previously associated with cervical cancer in a candidate gene study of PAX8-AS1 haplotypes [147].…”

“…Even where the causal variants were determined, it still remains a challenge to assign biological function to the variants and identify the causal gene(s). Attempts for fine-mapping or functional validation via chromatin conformation or eQTL analysis are only a handful so far [119,128,136,146,153,171].…”

“…Two weakly correlated variants, rs4848320 and rs1110839, had been previously associated with cervical cancer in a candidate gene study of PAX8-AS1 haplotypes [147]. In gene expression analyses, the variant rs10175462 presented as a cis-eQTL for the PAX8-AS1 non-coding RNA and also appeared to modulate PAX8 levels in response to HPV [146]. PAX8 is emerging as an important transcription factor also for other gynecological cancers [148] but more work will be required to elucidate its role in cervical cancer pathogenesis.…”

Association of two genomic variants with HPV subtype-specific risk of cervical cancer

“…We investigated a total of 1568 samples from the German Cervigen consortium 13 , including samples that had been collected in nine German hospitals in Hannover, Wolfsburg, Jena, Erlangen, Dresden, Halle, Munich, Berlin and Bad Münder. The HPV status of the patients was available along with other clinical variables.…”

Paired-Box Gene 8 (PAX8) and Its Association With Epithelial Carcinomas

“…Similarly, we can detect PAX8 upregulations in cervical cells infected with human papillomavirus (HPV) as viral proteins disrupt TP53 and RB1 functions. In a recent study, RNA analysis in cervical samples uncovered upregulation of PAX8 transcripts in HPV-positive lesions, presumed to be the main culprit behind cervical carcinoma [42]. Several studies reported PAX8 expression in adenocarcinoma, SCC, endometrioid adenocarcinoma, and adenosquamous carcinoma of the uterine cervix [13, 30-31, 38, 43-51].…”