Common Genetic Variants and Risk for HPV Persistence and Progression to Cervical Cancer

Abstract

HPV infrequently persists and progresses to cervical cancer. We examined host genetic factors hypothesized to play a role in determining which subset of individuals infected with oncogenic human papillomavirus (HPV) have persistent infection and further develop cervical pre-cancer/cancer compared to the majority of infected individuals who will clear infection.We evaluated 7140 tag single nucleotide polymorphisms (SNPs) from 305 candidate genes hypothesized to be involved in DNA repair, viral infection and cell entry in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 HPV persistent women (median: 25 months), and 425 random controls (RC) from the 10,049 women Guanacaste Costa Rica Natural History study. We used logistic regression to compute odds ratios and p-trend for CIN3/cancer and HPV persistence in relation to SNP genotypes and haplotypes (adjusted for age). We obtained pathway and gene-level summary of associations by computing the adaptive combination of p-values. Genes/regions statistically significantly associated with CIN3/cancer included the viral infection and cell entry genes 2′,5′ oligoadenylate synthetase gene 3 (OAS3), sulfatase 1 (SULF1), and interferon gamma (IFNG); the DNA repair genes deoxyuridine triphosphate (DUT), dosage suppressor of mck 1 homolog (DMC1), and general transcription factor IIH, polypeptide 3 (GTF2H4); and the EVER1 and EVER2 genes (p<0.01). From each region, the single most significant SNPs associated with CIN3/cancer were OAS3 rs12302655, SULF1 rs4737999, IFNG rs11177074, DUT rs3784621, DMC1 rs5757133, GTF2H4 rs2894054, EVER1/EVER2 rs9893818 (p-trends≤0.001). SNPs for OAS3, SULF1, DUT, and GTF2H4 were associated with HPV persistence whereas IFNG and EVER1/EVER2 SNPs were associated with progression to CIN3/cancer. We note that the associations observed were less than two-fold. We identified variations DNA repair and viral binding and cell entry genes associated with CIN3/cancer. Our results require replication but suggest that different genes may be responsible for modulating risk in the two critical transition steps important for cervical carcinogenesis: HPV persistence and disease progression.

Pathway-based analysis of genetic susceptibility to cervical cancer in situ: HLA-DPB1 affects risk in Swedish women

“…This points to the importance of the immune response toward HPV infection in preventing carcinoma development and explains why genetic variations in genes of immunological pathways, in addition to the HLA class II genes, [6][7][8][9][10][11][12] are associated with in situ (2011) 12, 605 -614. and invasive cervical cancer. 9,[14][15][16][17][18] However, only a handful of the identified genes show a consistent effect in multiple cohorts, and thus additional risk factors for persistent infection and tumor development are likely to exist. Assuming that variation in genes with a specific function is of particular interest, there are several optional study designs.…”

“…Assuming that variation in genes with a specific function is of particular interest, there are several optional study designs. Wang et al 15 studied the effect of 7146 tag single-nucleotide polymorphisms (SNPs) in 305 genes with a presumed function in DNA repair, viral infection and cell entry, on cervical cancer. The success of this approach relies on the criteria used for identification of candidate genes and on the SNP markers tagging functional variants of these genes.…”

An Updated Meta-Analysis: Cervical Cancer Risk Conferred by GSTM1 and GSTT1 Polymorphisms

“…(2) year of publication, (3) country and ethnicity, (4) sample size of cases and controls, (5) study design, and (6) genotyping methods used.…”

“…Previous studies have shown that DNA repair gene variants are associated with cervical cancer [4] . Indeed, functional variants of two xenobiotic metabolism genes, glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1), were associated with several cancers including cervical cancer.…”

Methylenetetrahydrofolate Reductase C677T Distribution among Cervical Cancer Patients at Dr. Hasan Sadikin General Hospital

“…As for host genetic factors, several genes are studied and may be responsible for cervical carcinogenesis, either in HPV persistence and disease progression. 7 One of the genes that is involved in this disease is the MTHFR gene that encodes an enzyme, that is the methylenetetrahydrofolate reductase enzyme which catalyzes 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate reaction. Hence, this enzyme determines folate coenzyme proportion for DNA synthesis or DNA methylation process as well as the abnormal DNA methylation process associated with carcinogenesis.…”