Article

Common Variants in Immune and DNA Repair Genes and Risk for Human Papillomavirus Persistence and Progression to Cervical Cancer

Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Rm. 5104, Rockville, MD 20852-7234, USA.
The Journal of Infectious Diseases (Impact Factor: 5.78). 12/2008; 199(1):20-30. DOI: 10.1086/595563
Source: PubMed

ABSTRACT We examined host genetic factors to identify those more common in individuals whose human papillomavirus (HPV) infections were most likely to persist and progress to cervical intraepithelial neoplasia grade 3 (CIN3) and cancer.
We genotyped 92 single-nucleotide polymorphisms (SNPs) from 49 candidate immune response and DNA repair genes obtained from 469 women with CIN3 or cancer, 390 women with persistent HPV infections (median duration, 25 months), and 452 random control subjects from the 10,049-woman Guanacaste Costa Rica Natural History Study. We calculated odds ratios and 95% confidence intervals (CIs) for the association of SNP and haplotypes in women with CIN3 or cancer and HPV persistence, compared with random control subjects.
A SNP in the Fanconi anemia complementation group A gene (FANCA) (G501S) was associated with increased risk of CIN3 or cancer. The AG and GG genotypes had a 1.3-fold (95% CI, 0.95-1.8-fold) and 1.7-fold (95% CI, 1.1-2.6-fold) increased risk for CIN3 or cancer, respectively (P(trend) = .008; referent, AA). The FANCA haplotype that included G501S also conferred increased risk of CIN3 or cancer, as did a different haplotype that included 2 other FANCA SNPs (G809A and T266A). A SNP in the innate immune gene IRF3 (S427T) was associated with increased risk for HPV persistence (P(trend) = .009).
Our results require replication but support the role of FANCA variants in cervical cancer susceptibility and of IRF3 in HPV persistence.

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    • "HPV infection is a necessary but not sufficient cause of cervical cancer . Whereas the vast majority of infected individuals naturally clear their infection(s), further research is warranted to distinguish risk factors that lead a subset of individuals infected with high risk HPV (HR-HPV) types to have persistent infection and later develop cervical lesions [1]. Functional variants of three xenobiotic metabolism genes such as cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), glutathione S-transferase mu 1 (GSTM1), and glutathione S-transferase theta 1 (GSTT1) have been associated with several cancers including cervical cancer but the results have been inconsistent [2] [3] [4] [5] [6]. "
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    ABSTRACT: Objective We evaluated time to clearance of high risk (HR) HPV infection in relation to functional variants in three genes (CYP1A1, GSTT1, and GSTM1). Methods The study group consisted of 450 HR-HPV infected women from the Atypical squamous cells of undetermined significance-low-grade squamous intraepithelial Lesion Triage Study (ALTS) cohort followed up at the clinical center at Birmingham, Alabama. The Cox proportional hazard model with the Wei-Lin-Weisfeld (WLW) approach was used, controlling for relevant covariates. Results Women who were polymorphic for CYP1A1 experienced an HR-HPV clearance rate that was 20% (HR = 0.80, p = 0.04) lower than women without the polymorphism for CYP1A1, adjusting for all other cofactors. The GSTM1 null genotype was associated with higher HR-HPV clearance rate (HR = 1.39, p = 0.006). The polymorphism in GSTT1 was not significantly associated with time to clearance of HR-HPV. Conclusions Xenobiotic metabolism genes may influence the natural history of HR-HPV infection and its progression to cervical cancer.
    Gynecologic Oncology 10/2014; 135(3). DOI:10.1016/j.ygyno.2014.09.015 · 3.69 Impact Factor
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    • "With the step of screening the title, abstract or content, 5 eligible studies were selected. Manual search of references cited in 1 additional article, but it was excluded for lack of data about XRCC3 Thr241Met gene polymorphism of cervical cancer (Wang et al., 2009). Finally, a total of 5 relevant studies including 4 English articles (He et al., 2008; Settheetham-Ishida et al., 2011; Djansugurova et al., 2013; Perez et al., 2013) and 1 Chinese paper (Xiao et al., 2010) met the inclusion criteria for the meta-analysis (including a total of 806 cervical cancer cases and 850 controls). "
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    ABSTRACT: Background: Numerous epidemiological studies have been conducted to evaluate the association between variants of the DNA repair gene XRCC3 and cancer risk. Here we focused on one XRCC3 polymorphism and development of cervical cancer, performing a meta-analysis. Methods: The pooled association between the XRCC3 Thr241Met polymorphism and cervical cancer risk was assessed by odds ratios (ORs) and their 95% confidence intervals (95%CIs). Results: A total of 5 case-control studies met the inclusion criteria. The pooled ORs for the total included studies showed no association among homozygotes TT vs. CC: OR=1.93, 95%CI=0.68- 5.49, P=0.22; dominant model TT<TC vs. CC: OR=1.37, 95%CI=0.90-2.06, P=0.14; and recessive model TT vs. TC<CC: OR=1.76, 95%CI=0.68-4.55, P=0.25, but might be a slight risk factor for cervical cancer in heterozygote contrast TT vs. CT: OR= 1.33, 95%CI=1.04-1.71, P=0.02. In subgroup analysis, significant associations were found for Asians under all genetic models. Conclusions: Our meta-analysis suggested the XRCC3 Thr241Met polymorphism might not act as a cervical cancer risk factor overall. However, in subgroup analysis, a significant association was found in Asians under all genetic models. The association should be studied with a larger, stratified population, especially for Asians.
    Asian Pacific journal of cancer prevention: APJCP 11/2013; 14(11):6703-7. DOI:10.7314/APJCP.2013.14.11.6703 · 2.51 Impact Factor
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    • "We performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and cervical lesions risk. Twenty case-control studies with a total of 4,146 cases and 4,731 controls were finally included into the meta-analysis [13]–[25], [30]–[34]. Overall, TNF-α rs1800629 polymorphism was significantly associated with increased risk of cervical lesions under two main genetic comparison models (Table 2). "
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    PLoS ONE 08/2013; 8(8):e69201. DOI:10.1371/journal.pone.0069201 · 3.23 Impact Factor
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