Novel variants in the PAX8, CLPTM1L, and HLA genes are associated with a high risk of developing cervical cancer, according to a study published in The Lancet Oncology.

According to the study authors, a majority of uterine, cervical, high-risk human papillomavirus (HPV) infections are transient and are cleared through an incompletely understood immune response. However, some women with HPV develop a persistent infection that ultimately progresses to cervical intraepithelial neoplasia (CIN) or invasive cervical cancer, which is thought to involve a significant inherited genetic component.

Although previous genome-wide association studies (GWASs) of cervical preinvasive and invasive disease performed worldwide showed an association between the HLA region and cervical cancer, these studies were limited because of smaller sample sizes and the low number of invasive cases with inconsistent results, the study authors explained.

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Using a genome-wide approach, researchers assessed genetic variations in women with invasive cervical cancer and grade 3 cervical intraepithelial neoplasia (CIN3) and compared them with genetic variations in healthy individuals. The researchers conducted a GWAS in a cohort of unrelated European individuals, using data from the UK Biobank that included 4769 CIN3 and invasive cervical cancer case samples and 145,545 control samples.

Among the 9,600,464 samples assayed and imputed single-nucleotide polymorphisms, 6 independent variants were found to be linked to CIN3 and invasive cervical cancer. Of these, 2 were novel loci rs10175462 (PAX8; odds ratio [OR], 0.8; 95% CI, 0.84-0.91; =1.07×10–9) and rs27069 (CLPTM1L; OR, 0.8; 95% CI, 0.84-0.92; P =2.51×10–9), and 4 were previously reported signals at rs9272050 (HLA-DQA1; OR, 1.27; 95% CI, 1.21-1.32; P =2.51×10-28), rs6938453 (MICA; OR, 0.79; 0.75-0.83; P =1.97×10–17), rs55986091 (HLA-DQB1; OR, 0.66; 95% CI, 0.60-0.72; P =6.42×10–22), and rs9266183 (HLA-B; OR, 0.73; 95% CI, 0.64-0.83; P =1.53×10-6).

In the independent dataset that included 1648 invasive cervical cancer cases and 121,931 control samples, a significant association was identified for 3 variants — PAX8 (rs10175462; P =.015), CLPTM1L (rs27069; P =2.54×10-7), and HLA-DQA1 (rs9272050; P =7.90 × 10–8).

In the Mendelian randomization analysis of exposures associated with CIN3 and invasive cervical cancer, the strongest associations with the risk of cervical cancer were observed for smoking (OR, 2.46; 95% CI, 1.64-3.69), the number of sexual partners (OR, 1.95; 1.44-2.63), and older age at first pregnancy (OR, 0.8; 0.68-0.95).

“Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways,” the study authors wrote. “Future studies integrating host and viral, genetic, and epigenetic variation could further elucidate complex host-viral interactions.” 

Disclosures: This research was supported AbbVie, AstraZeneca UK, Biogen MA, Celgene Corporation, Celgene International II Sàrl, Genentech, Merck Sharp & Dohme Corp, Pfizer, GlaxoSmithKline, Sanofi, Maze Therapeutics, and Janssen Biotech. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Bowden SJ, Bodinier B, Kalliala I, et al; FinnGen consortium. Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study. Lancet Oncol. 2021;22(4):548-557. doi:10.1016/S1470-2045(21)00028-0