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1.  The Association Between -1304T>G Polymorphism in the Promoter of Mitogen-Activated Protein Kinase Kinase 4 Gene and the Risk of Cervical Cancer in Chinese Population 
DNA and Cell Biology  2012;31(7):1167-1173.
Mitogen-activated protein kinase kinase 4 (MKK4) is a critical mediator of stress-activated protein kinase signals that regulate apoptosis, inflammations, and tumorigenesis. Several polymorphisms have been identified in the MKK4 gene. We hypothesized that genetic variants in the MKK4 promoter may alter its functions and thus cancer risk. In the current, hospital-based case-control study of 471 cervical cancer cases and 600 sex and age frequency-matched cancer-free controls in an Eastern Chinese population, we genotyped two common polymorphisms in the MKK4 promoter region (-1304T>G, rs3826392 and -1044A>T, rs3809728)c and assessed their associations with the risk of cervical cancer. We found that compared with the most common -1304TT genotype, carriers of -1304G variant genotypes had a significantly decreased risk of cervical cancer [odds ratio (OR)=0.71; 95% confidence interval (CI)=0.53–0.92 for TG, and OR=0.52; 95%CI=0.30–0.91 for GG] in an allele dose-response manner (adjusted Ptrend=0.004). Moreover, the luciferase assay showed that the G allele in the promoter significantly increased the transcription activity of the MKK4 gene in vitro and that the MKK4 mRNA expression levels of the G variant carriers was significantly higher in tumor tissues than those of the -1304TT genotype. However, no significant association was observed between the -1044A>T polymorphism and risk of cervical cancer. Our data suggest that the functional -1304G variant in the MKK4 promoter contributes to a decreased risk of cervical cancer by increasing the promoter activity and that the G variant may be a marker for susceptibility to cervical cancer.
doi:10.1089/dna.2011.1586
PMCID: PMC3391489  PMID: 22335172
2.  Analysis of Tp53 Codon 72 Polymorphisms, Tp53 Mutations, and HPV Infection in Cutaneous Squamous Cell Carcinomas 
PLoS ONE  2012;7(4):e34422.
Background
Non-melanoma skin cancers are one of the most common human malignancies accounting for 2–3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas.
Methods
We studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism).
Results
We found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R.
Conclusions
These studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations.
doi:10.1371/journal.pone.0034422
PMCID: PMC3335843  PMID: 22545084
3.  Inverse Association between Methylation of Human Papillomavirus Type 16 DNA and Risk of Cervical Intraepithelial Neoplasia Grades 2 or 3 
PLoS ONE  2011;6(8):e23897.
Background
The clinical relevance of human papillomavirus type 16 (HPV16) DNA methylation has not been well documented, although its role in modulation of viral transcription is recognized.
Methods
Study subjects were 211 women attending Planned Parenthood clinics in Western Washington for routine Papanicolaou screening who were HPV16 positive at the screening and/or subsequent colposcopy visit. Methylation of 11 CpG dinucleotides in the 3′ end of the long control region of the HPV16 genome was examined by sequencing the cloned polymerase chain reaction products. The association between risk of CIN2/3 and degree of CpG methylation was estimated using a logistic regression model.
Results
CIN2/3 was histologically confirmed in 94 (44.5%) of 211 HPV16 positive women. The likelihood of being diagnosed as CIN2/3 increased significantly with decreasing numbers of methylated CpGs (meCpGs) in the 3′ end of the long control region (Pfor trend = 0.003). After adjusting for HPV16 variants, number of HPV16-positive visits, current smoking status and lifetime number of male sex partners, the odds ratio for the association of CIN2/3 with ≥4 meCpGs was 0.31 (95% confidence interval, 0.12–0.79). The proportion of ≥4 meCpGs decreased appreciably as the severity of the cervical lesion increased (Pfor trend = 0.001). The inverse association remained similar when CIN3 was used as the clinical endpoint. Although not statistically significant, the ≥4 meCpGs-related risk reduction was more substantial among current, as compared to noncurrent, smokers.
Conclusion
Results suggest that degree of the viral genome methylation is related to the outcome of an HPV16 cervical infection.
doi:10.1371/journal.pone.0023897
PMCID: PMC3161083  PMID: 21887341
4.  DNA methylation changes in normal liver tissues and hepatocellular carcinoma with different viral infection 
Hepatocellular carcinoma (HCC) is known to be associated with both HBV and HCV and HVC. While epigenetic changes have been previously reported to be associated with hepatocellular carcinoma (HCC), whether the epigenetic profile of HBC associated HCC differs from that of HCV associated HCC is unclear. We analyzed DNA methylation of ten genes (APC, CCND2, CDKN2A, GSTP1, HOXA9, RARB, RASSF1, RUNX, SFRP1, and TWIST1) using MethyLight assays on 65 archived liver tissue blocks. Three genes (APC, CCND2, and GSTP1) were frequently methylated in normal liver tissues. Five genes (APC, CDKN2A, HOXA9, RASSF1, and RUNX) were significantly more frequently methylated in malignant liver tissues than normal liver tissues. Among HCC cases, HOXA9, RASSF1 and SFRP1 were methylated more frequently in HBV positive HCC cases, while CDKN2A were significantly more frequently methylated in HCV positive HCC cases. Our data support the hypothesis that HCC resulting from different viral etiologies are associated with different epigenetic changes.
doi:10.1016/j.yexmp.2010.01.002
PMCID: PMC2848881  PMID: 20079733
hypermethylation; HBV; HCV; hepatocellular carcinoma
5.  Identification of Recombinant Human Papillomavirus Type 16 Variants 
Virology  2009;394(1):8-11.
Intratypic diversity of human papillomavirus (HPV) genome is generally characterized by point mutation, insertion, and/or deletion. Using PCR-based cloning and sequencing, we detected concurrent infection with 8 HPV16 variants in a woman enrolled in the ASCUS-LSIL Triage Study. The European variant was the major variant; each of the seven minor variants had partial DNA sequences identical to the European variant and another part identical to the African-2 variant. At a follow-up visit, only an HPV16 African-2 variant was detected. Results from the present study suggest presence of intratypic recombination of HPV genome in natural infection.
doi:10.1016/j.virol.2009.08.040
PMCID: PMC2769496  PMID: 19758676
human papillomavirus; recombination; variant
6.  Sequence Variation of Human Papillomavirus Type 16 and Measurement of Viral Integration by Quantitative PCR▿  
Journal of Clinical Microbiology  2008;47(3):521-526.
Given that the integration of human papillomavirus type 16 (HPV16) into the host genome occurs preferentially with the disruption of the E2 gene, a ratio of E2 to E7 gene copies is often used as a marker for integration. It is largely undetermined, however, whether ratio estimates are affected by HPV intratypic variations. We assembled four plasmid constructs, each containing a DNA fragment from an HPV16 European, Asian-American, African-1, or African-2 variant. These constructs and nine cervical swab samples were assayed by real-time PCR with two primer-probe sets for each gene: a specific set, fully complementary to the HPV16 prototype, and a degenerate set, incorporating degenerate bases at positions where nucleotides differed among the variants. The ratio of E2 to E7 gene copies for the European variant construct was close to 1, no matter which sets of primers and probes were used. While the ratios for the African-1 and Asian-American variant constructs remained close to 1 with the degenerate sets of primers and probes, the ratios were 0.36 and 2.57, respectively, with the specific sets of primers and probes. In addition, a nucleotide alteration at the position immediately following the 3′ end of the E2 forward primer binding site was found to be responsible for an underestimation of E2 gene copies for the African-2 variant construct. Similar patterns were found in nine cervical samples. In conclusion, mismatches between the primers and probes and their targets due to HPV16 intratypic variations would introduce errors in testing for integration; this situation can be sufficiently ameliorated by incorporating degenerate bases into the primers and probes.
doi:10.1128/JCM.02115-08
PMCID: PMC2650947  PMID: 19116350

Results 1-6 (6)