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Genome-Wide Association Study of Variants Linked to Cervical Preinvasive and Invasive Disease


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In a genome-wide association study reported in The Lancet Oncology, Bowden et al identified six independent variants among the PAX8, CLPTM1L, and HLA genes that were associated with risk for invasive cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3).

As stated by the investigators, “Most uterine cervical high-risk human papillomavirus infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and CIN3 with that in healthy controls.”

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. Future studies integrating host and viral, genetic, and epigenetic variation could further elucidate complex host-viral interactions.
— Bowden et al

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Study Details

The genome-wide association study involved UK Biobank data on 4,769 CIN3 or invasive cervical cancer case samples and 145,545 control samples without CIN3 or invasive disease. The women in the cohort were aged 40 to 69 years at recruitment between March 2006 and October 2010. An additive univariate logistic regression model was used to analyze genetic variants associated with invasive cervical cancer or CIN3.

Key Findings

Among 9,600,464 assayed and imputed single-nucleotide polymorphisms, six independent variants were associated with CIN3 or invasive cervical cancer. Two of these were the novel loci rs10175462 in PAX8 (odds ratio [OR] = 0.87, P = 1.07 × 10-9) and rs27069 in CLPTM1L (OR = 0.88, P = 2.51 × 10-9). Four were previously reported signals in the HLA region: at rs9272050 in HLA-DQA1 (OR = 1.27, P = 2.51 × 10-28), rs6938453 in MICA (OR = 0.79, P = 1.97 × 10-17), rs55986091 in HLA-DQB1 (OR = 0.66, P = 6.42 × 10-22), and rs9266183 in HLA-B (OR = 0.73, P = 1.53 × 10-6).

In an independent dataset (FinnGen) including 1,648 invasive cervical cancer cases and 121,931 controls, significant associations were found for three of the single-nucleotide polymorphisms: rs10175462 in PAX8 (P = .015), rs27069 in CLPTM1L (P = 2.54 × 10-7), and rs9272050 in HLA-DQA1 (P = 7.90 × 10-8).

A Mendelian randomization was performed using established environmental risk factors and genetic variants with known effects on the risk factors, with the randomization including 62 risk factors and genetic data from three genome-wide association studies. The strongest associations with risk of cervical cancer were observed for smoking (OR = 2.46, 95% confidence interval [CI] = 1.64–3.69) and number of sexual partners (OR = 1.95, 95% CI = 1.44–2.63), with a protective effect observed for older age at first pregnancy (OR = 0.80, 95% CI = 0.68–0.95).

The investigators concluded, “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. Future studies integrating host and viral, genetic, and epigenetic variation could further elucidate complex host-viral interactions.”

Maria Kyrgiou, PhD, of the Institute of Reproductive and Developmental Biology, Imperial College London, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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