p16 hypermethylation: A biomarker for increased esophageal cancer susceptibility in high incidence region of North East India
Esophageal cancer is one of the most common cancers in North East India. The molecular mechanisms of esophageal cancer susceptibility in North East India have not been fully understood. There is a need for identification of biomarkers to identify people at risk of esophageal cancer. p16 is an essential G1 cell cycle regulatory gene whose loss of function is associated with carcinogenesis. Therefore, we conducted this study to determine the prevalence of p16 gene methylation in patients with esophageal cancer to assess the feasibility of using gene methylation as a biomarker. A total of 100 newly diagnosed esophageal cancer cases along with equal number of age, sex, and ethnicity-matched controls were included in this study. Methylation-specific PCR was used to determine the p16 methylation status. Aberrant promoter methylation of the p16 gene was detected in 81 of 100 (81 %) esophageal cancer cases. Hypermethylation of p16 gene was found to be influenced by lifestyle factors. Betel quid and tobacco chewing habit synergistically with p16 methylation elevated the risk for esophageal cancer development (adjusted odds ratio (OR) = 6.88, 95 % confidence interval (CI) = 1.64–28.81, p = 0.003 for betel quid chewing and adjusted OR = 7.02, 95 % CI = 1.87–26.38, p = 0.001 for tobacco chewing). Further, intake of green leafy vegetables and fruits lowered the risk of esophageal cancer (adjusted OR = 0.16, 95 % CI = 0.04–0.58, p = 0.05 for green leafy vegetables and adjusted OR = 0.15, 95 % CI = 0.04–0.64, p = 0.01 for fruits). Thus, p16 hypermethylation may aid as a biomarker in identifying habitués at greater risk for esophageal cancer susceptibility in high incidence region of North East India.
KeywordsEsophageal cancer North East India p16 gene Methylation Biomarker
This work was supported by the Indian Council of Medical Research (ICMR), Department of Health Research and Government of India under the extramural funding of Northeast Initiative. We would like to thank Dr. Nirmal Sahewala (Consultant Radiologist, Obsteristics and Gynecology) and Dr. Bimal Kumar Jalan (Chief Endoscopist), Aditya Hospital, Dibrugarh, Assam, India, for their support during sample collection. We would also like to thank the staff of Radiology Department, Assam Medical College and Hospital, Dibrugarh, Assam, India.
Conflicts of interest
- 1.Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC Cancer Base No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer 2012. http://globocan.iarc.fr. Accessed 11 Jul 2014.
- 2.NCRP. National cancer registry programme (NCRP) three year report of population based cancer registries : 2009–2011.Google Scholar
- 7.Adams L, Roth MJ, Abnet CC, Dawsey SP, Qiao YL, Wang GQ, et al. Promoter methylation in cytology specimens as an early detection marker for esophageal squamous dysplasia and early esophageal squamous cell carcinoma. Cancer Prev Res (Phila). 2008;1(5):357–61. doi: 10.1158/1940-6207.CAPR-08-0061.CrossRefPubMedCentralGoogle Scholar
- 15.Morey Kinney SR, Smiraglia DJ, James SR, Moser MT, Foster BA, Karpf AR. Stage-specific alterations of DNA methyltransferase expression, DNA hypermethylation, and DNA hypomethylation during prostate cancer progression in the transgenic adenocarcinoma of mouse prostate model. Mol Cancer Res. 2008;6(8):1365–74. doi: 10.1158/1541-7786.MCR-08-0040.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Ai L, Stephenson KK, Ling W, Zuo C, Mukunyadzi P, Suen JY, et al. The p16 (CDKN2a/INK4a) tumor-suppressor gene in head and neck squamous cell carcinoma: a promoter methylation and protein expression study in 100 cases. Mod Pathol. 2003;16(9):944–50. doi: 10.1097/01.MP.0000085760.74313.DD.CrossRefPubMedGoogle Scholar
- 32.Wang J, Sasco AJ, Fu C, Xue H, Guo G, Hua Z, et al. Aberrant DNA methylation of P16, MGMT, and hMLH1 genes in combination with MTHFR C677T genetic polymorphism in esophageal squamous cell carcinoma. Cancer Epidemiol Biomark Prev. 2008;17(1):118–25. doi: 10.1158/1055-9965.EPI-07-0733.CrossRefGoogle Scholar
- 33.NCRP. National cancer registry programme (NCRP) three year report of population based cancer registries: 2006–2008.Google Scholar
- 35.Lin RK, Hsieh YS, Lin P, Hsu HS, Chen CY, Tang YA, et al. The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. J Clin Invest. 2010;120(2):521–32. doi: 10.1172/JCI40706.CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Stidley CA, Picchi MA, Leng S, Willink R, Crowell RE, Flores KG, et al. Multivitamins, folate, and green vegetables protect against gene promoter methylation in the aerodigestive tract of smokers. Cancer Res. 2010;70(2):568–74. doi: 10.1158/0008-5472.CAN-09-3410.CrossRefPubMedPubMedCentralGoogle Scholar