Immuno-related polymorphisms and cervical cancer risk: The IARC multicentric case-control study.

James Mckay,Tarik Gheit,Sandrine Chopin,Silvia Franceschi,Uzma Hasan,Michelle Ainouze,Salvatore Vaccarella,Vanessa Tenet,Patrice H Avogbe,Massimo Tommasino,Valérie Gaborieau,Amélie Chabrier

doi:10.1371/journal.pone.0177775

Abstract

A small proportion of women who are exposed to infection with human-papillomavirus (HPV) develop cervical cancer (CC). Genetic factors may affect the risk of progression from HPV infection to cervical precancer and cancer. We used samples from the International Agency for Research on Cancer (IARC) multicentric case-control study to evaluate the association of selected genetic variants with CC. Overall, 790 CC cases and 717 controls from Algeria, Morocco, India and Thailand were included. Cervical exfoliated cells were obtained from control women and cervical exfoliated cells or biopsy specimens from cases. HPV-positivity was determined using a general primer GP5+/6+ mediated PCR. Unconditional logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) of host genotypes with CC risk, using the homozygous wild type genotype as the referent category and adjusting by age and study centre. The association of polymorphisms with the risk of high-risk HPV-positivity among controls was also evaluated. A statistically significant association was observed between single nucleotide polymorphism (SNP) CHR6 rs2844511 and CC risk: the OR for carriers of the GA or GG genotypes was 0.70 (95% CI: 0.43–1.14) and 0.61 (95% CI: 0.38–0.98), respectively, relative to carriers of AA genotype (p-value for trend 0.03). We also observed associations of borderline significance with the TIPARP rs2665390 polymorphism, which was previously found to be associated with ovarian and breast cancer, and with the EXOC1 rs13117307 polymorphism, which has been linked to cervical cancer in a large study in a Chinese population. We confirmed the association between CC and the rs2844511 polymorphism previously identified in a GWAS study in a Swedish population. The major histocompatibility region of chromosome 6, or perhaps other SNPs in linkage disequilibrium, may be involved in CC onset.

Highlights

The burden of cervical cancer (CC) has decreased considerably over recent decades in countries that have implemented high-quality cytology screening programmes [1, 2], it remains the fourth most commonly diagnosed cancer worldwide among women and the most common site in several low-income countries [3]
For two other single nucleotide polymorphism (SNP), TIPARP rs2665390 and EXOC1 rs13117307, we found associations of borderline statistical significance (p-values 0.05 and 0.06, respectively), with TC carriers of TIPARP rs2665390 showing an increased risk of CC (ORTC = 1.41, 95% confidence intervals (CI): 1.00–1.99) as compared to TT carriers, and with CT and TT carriers in EXOC1 rs13117307 showing a reduced risk (ORCT = 0.81, 95% confidence intervals (95% CI): 0.63–1.03; ORTT = 0.72, 95% CI: 0.36–1.45)
In this international multicentric case-control study of CC that included women from Morocco, Algeria, India and Thailand, we confirmed the association of the rs2844511 polymorphism previously identified in a GWAS study in a Sweden population [10] with CC

Summary

Introduction

The burden of cervical cancer (CC) has decreased considerably over recent decades in countries that have implemented high-quality cytology screening programmes [1, 2], it remains the fourth most commonly diagnosed cancer worldwide among women and the most common site in several low-income countries [3]. Persistent infection with high-risk human papillomavirus (HR-HPV) types is a necessary cause of CC. Genital infection with HPV is very common among the general female population, but only a small fraction of women develop a persistent infection [5] and are subsequently at risk for progression to precancer and invasive CC. Other factors in addition to HPV are likely to be involved in progression from an infected cell to a transformed cell with invasive potential. There is a relatively large amount of information on the role of non-genetic co-factors [6,7,8,9], only a few studies, mainly targeting Caucasian or Chinese populations, have explored the association between host genetics, in particular host immune molecules, and the pathogenesis of CC [10,11,12]

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