Evaluation of p16INK4α Hypermethylation from Liquid-based Pap Test Samples in Vietnamese Population
Abstract
Background: Human papillomavirus (HPV) infection has been considered as main cause of cervical cancer. Recently, aberrant DNA methylation at tumor suppressor genes (TSGs), leading to inactivation, has also been an early epigenetic event and cofactor in cervical carcinogenesis. This study was performed to evaluate an association between the hypermethylation of p16INK4α gene’s promoter and HPV exposure in non-invasive samples (liquid-based papanicolaous samples) in Vietnamese population.
Methods: 109 liquid-based papanicolaous test samples were archived and admitted from the Medic Medical Center and Au Lac Clinic Laboratory, Vietnam, from 2011–2014. Methylation-Specific-PCR (MSP) was performed to analyze methylation status from the liquid-based papanicolaous test samples identified whether HPV/or non-HPV, high-risk/low-risk HPV infection.
Results: An upward trend was observed concerning the p16INK4α hypermethylation frequency in high-risk HPV infection, counting for 55.6%, and the low methylation frequency in low-risk and non-HPV infected samples, counting for 22.9%, 8.0%, respectively. The significant correlation between candidate p16INK4α hypermethylation and HPV exposure was observed (P<0.0001). Moreover, the odds ratio (OR) and relative risk (RR) were found in statistical significant value. (OR=5.76, 95%CI: 2.36 – 14.04, P<0.01; RR=3.11, 95%CI: 1.75–5.53, P<0.01).
Conclusion: Presence of p16INK4α hypermethylation was the specific characteristic of high-risk HPV infected samples in Vietnamese population. The OR and RR values showed that the strong correlation between p16INK4α hypermethylation and high-risk HPV infection, in which increased the risk of cervical cancer. The combination of p16INK4α hypermethylation and HPV detection based biomarker could be used in non-invasive samples obtained from high-risk cancer patients, offer significant practical advantages.
Burd EM (2003). Human papillomavirus and cervical cancer. Clin Microbiol Rev, 16 (1): 1-17.
Castle PE, Maza M (2016). Prophylactic HPV vaccination: past, present, and future. Epidemiol Infect, 144(3):449-68.
Ingles DJ, Pierce Campbell CM, et al (2015). Human papillomavirus virus (HPV) genotype- and age-specific analyses of external genital lesions among men in the HPV Infection in Men (HIM) Study. J Infect Dis, 211 (7): 1060-7.
Jenkins D (2008). A review of cross-protection against oncogenic HPV by an HPV-16/18 AS04-adjuvanted cervical cancer vaccine: Importance of virological and clinical endpoints and implications for mass vaccination in cervical cancer prevention. Gynecol Oncol, 110(3 Suppl 1):S18-25.
Lao DT, Truong PK, Nguyen AQT, Sharma N, Le HAT (2013). DNA Methylation at the RARβ Promoter: A Potential Biomarker for Cervical Cancer. Current Trends in Biotechnology and Pharmacy, 7 (3): 708-15.
Zur Hausen H (1996). Papillomavirus infections-a major cause of human cancers. Biochim Biophys Acta, 1288 (2): F55-78.
Fleischhacker M1, Schmidt B (2007). Circulating nucleic acids (CNAs) and cancer--a survey. Biochim Biophys Acta, 1775(1):181-232.
Dueñas-González A, Lizano M, Candelaria M, Cetina L, Arce C, Cervera E (2005). Epigenetics of cervical cancer. An overview and therapeutic perspectives. Mol Cancer, 4: 38.
Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG (2001). Aberrant patterns of DNA methylation, chromatin for-mation and gene expression in cancer. Hum Mol Genet, 10 (7): 687-92.
Esteller M, Corn PG, Baylin SB, Herman JG (2001). A gene hypermethylation profile of human cancer. Cancer Res, 61 (8): 3225-9.
Lu Q, Ma D, Zhao S (2012). DNA methylation changes in cervical cancers. Methods Mol Biol, 863: 155-76.
Nuovo GJ, Plaia TW, Belinsky SA, Baylin SB, Herman JG (1999). In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc Natl Acad Sci USA, 96: 12754-9.
Truong PK, Lao TD, Doan TP, Le TA (2014). BRCA1 promoter hypermethylation signature for early detection of breast cancer in the Vietnamese population. Asian Pac J Cancer Prev, 15 (22): 9607-10.
Truong PK, Lao TD, Doan TP, Le TA (2015). Loss of expression of cyclin d2 by aberrant DNA methylation: a potential biomarker in Vietnamese breast cancer patients. Asian Pac J Cancer Prev, 16 (6): 2209-13.
Jiaying Lin, Andreas E. Albers, Jinbao Qin, Andreas M. Kaufmann (2014). Prognostic Significance of Overexpressed p16INK4a in Patients with Cervical Cancer: A Meta-Analysis. PLoS One, 9 (9): e106384.
Narayan G, Arias-Pulido H, Koul S, Vargas H, Zhang FF, Villella J, Schneider A, Terry MB, Mansukhani M, Murty VV (2003). Frequent promoter methylation of CDH1, DAPK, RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome. Mol Cancer, 2: 24.
Ohtani N, Yamakoshi K, Takahashi A, Hara E (2014). The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. J Med Invest, 51 (3-4): 146-53.
Serrano M, Hannon GJ, Beach D (1993). A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature, 366: 704-7.
Jha AK, Nikbakht M, Jain V, Capalash N, Kaur J (2012). p16INK4a and p15INK4b gene promoter methylation in cervical cancer patients. Oncol Lett, 3 (6): 1331-5.
Attaleb M, El hamadani W, Khyatti M, Benbacer L, Benchekroun N, Benider A, Amrani M, El Mzibri M (2009). Status of p16(INK4a) and E-cadherin gene promoter methylation in Moroccan patients with cervical carcinoma. Oncol Res, 2009; 18 (4): 185-92.
Jeong DH, Youm MY, Kim YN, Lee KB, Sung MS, Yoon HK, Kim KT (2006). Promoter methylation of p16, DAPK, CDH1, and TIMP-3 genes in cervical cancer: correlation with cli-nicopathologic characteristics. Int J Gynecol Cancer, 16 (3): 1234-40.
Yoder JA, Walsh CP, Bestor TH (1997). Cytosine methylation and the ecology of intragenomic parasites. Trends Genet, 13 (8): 335-40.
Jones PA, Laird PW (1999). Cancer epigenetics comes of age. Nat Genet, 21(2): 163-7.
Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB (1996). Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A, 93(18): 9821-6.
Galm O, Herman JG. Methylation-specific poly-merase chain reaction. Methods Mol Med, 2005: 113:279-91.
Kahn SL, Ronnett BM, Gravitt PE, Gustafson KS (2008). Quantitative methylation-specific PCR for the detection of aberrant DNA methylation in liquid-based Pap tests. Cancer, 114 (1): 57-64.
Qureshi SA, Bashir MU, Yaqinuddin A (2010). Utility of DNA methylation markers for diagnosing cancer. Int J Surg, 8 (3): 194-8.
Schwarzenbach H, Pantel K (2015). Circulating DNA as biomarker in breast cancer. Breast Cancer Res, 17: 136.
Carestiato FN, Afonso LA, Moysés N, Almeida GL, Velarde LGC, Cavalcanti SMB (2013). An upward trend in DNA p16INK4α methylation pattern and high risk hpv infection according to the severity of the cervical lesion. Rev Inst Med Trop Sao Paulo, 55(5): 329-34.
Szalmás A, Kónya J (2009). Epigenetic alterations in cervical carcinogenesis. Semin Cancer Biol, 19(3): 144-52.
Burgers WA, Blanchon L, Pradhan S, Y de Launoit, Kouzarides T, Fuks F (2007). Viral oncoproteins target the DNA methyltransferases. Oncogene, 26(11): 1650-5.
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| Issue | Vol 46 No 9 (2017) | |
| Section | Original Article(s) | |
| Keywords | ||
| Cervical cancer Hypermethylation MSP p16INK4α Vietnamese population | ||
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