Date Published: January 13, 2010
Publisher: Public Library of Science
Author(s): Sophia S. Wang, Paula Gonzalez, Kai Yu, Carolina Porras, Qizhai Li, Mahboobeh Safaeian, Ana Cecilia Rodriguez, Mark E. Sherman, Concepcion Bratti, Mark Schiffman, Sholom Wacholder, Robert D. Burk, Rolando Herrero, Stephen J. Chanock, Allan Hildesheim, Syed A. Aziz. http://doi.org/10.1371/journal.pone.0008667
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.
Partial Text: Persistent infection with one of approximately 15 types of human papillomavirus (HPV) is necessary for the development of cervical cancer and its immediate precursor, cervical intraepithelial neoplasia grade 3 (CIN3). However, HPV infection is not a sufficient cause of cervical cancer/CIN3 and HPV cofactors have been identified, including oral contraceptive use and smoking . Familial aggregation studies and evaluation of inherited genetic variations further suggest that host genetic factors may also contribute to cervical cancer pathogenesis . A number of studies have evaluated and implicated a role for human leukocyte antigens (HLA) , . We previously reported the association between common variants in genes influencing DNA damage, notably, FANCA, associated with both HPV persistence and progression to CIN3/cancer. We also reported a variant in the innate immunity gene IRF3 associated with HPV persistence . Here, we expand our evaluation of host genetic variations in DNA repair, viral infection and cell entry genes and risk for HPV persistence and cervical precancer/cancer.
In this population-based study, we found nine genes/regions associated with CIN3/cancer, 6 of which remained significant at a FDR≤0.2 – three DNA repair genes (GTF2H4, DUT, and DMC1) and three viral infection and cell entry related genes (OAS3, SULF1, and IFNG). A unique aspect of our study is the ability to separately evaluate associations with the two important transition steps in the natural history of cervical cancer – viral persistence and progression to precancer/cancer. Of the regions/genes found to be important, the association was primarily with HPV persistence for GTF2H4 and SULF1. IFNG and the epidermodysplasia verruciformis (EV)-associated genes (TMC6-EVER1 and TMC8-EVER2) were primarily associated with progression to CIN3/cancer. All top genes derived from the gene/region- and SNP-based analyses are annotated and briefly described in Table 4.
We sincerely thank Drs. Chris Buck and Patricia Day for their scientific contributions in suggesting candidate genes for evaluation with regard to their relevance in HPV binding. We are grateful to Sabrina Chen from the Information Management Services, Inc. (IMS) for data management and programming support. We are grateful to Amy Hutchinson and Belynda Hicks for their management of this genotyping effort at the NCI Core Genotyping Facility and for their scientific contributions to our research efforts. Results were presented in part at the 25th International Papillomavirus Conference, Malmo, Sweden, May 2009.