Lifestyle chemical carcinogens associated with mutations in cell cycle regulatory genes increases the susceptibility to gastric cancer risk
- 100 Downloads
In the present study, we correlated the various lifestyle habits and their associated mutations in cell cycle (P21 and MDM2) and DNA damage repair (MLH1) genes to investigate their role in gastric cancer (GC). Multifactor dimensionality reduction (MDR) analysis revealed the two-factor model of oral snuff and smoked meat as the significant model for GC risk. The interaction analysis between identified mutations and the significant demographic factors predicted that oral snuff is significantly associated with P21 3′UTR mutations. A total of five mutations in P21 gene, including three novel mutations in intron 2 (36651738G > A, 36651804A > T, 36651825G > T), were identified. In MLH1 gene, two variants were identified viz. one in exon 8 (37053568A > G; 219I > V) and a novel 37088831C > G in intron 16. Flow cytometric analysis predicted DNA aneuploidy in 07 (17.5%) and diploidy in 33 (82.5%) tumor samples. The G2/M phase was significantly arrested in aneuploid gastric tumor samples whereas high S-phase fraction was observed in all the gastric tumor samples. This study demonstrated that environmental chemical carcinogens along with alteration in cell cycle regulatory (P21) and mismatch repair (MLH1) genes may be stimulating the susceptibility of GC by altering the DNA content level abnormally in tumors in the Mizo ethic population.
KeywordsChemical carcinogens Gastric cancer Flow cytometer Cell cycle Mutation Mizo population
This work was supported by DBT—Advanced Level State Biotech Hub (BT/04/NE/2009 dt. 29.08.2014), Bioinformatics Infrastructure Facility (No. BT/BI/12/060/2012 (BTISNeT), and DBT eLibrary Consortium (DeLCON) sponsored by the Department of Biotechnology (DBT), New Delhi, Govt. of India, Mizoram University which provided all the essential facilities to carry out the work.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest to report.
Ethics, consent, and permissions
All participants gave written informed consent to the study protocol which was approved by the Ethical Committee of the Civil Hospital, Mizoram and Mizoram University, India (B.12018/1/13-CH(A)/IEC), to conduct and publish the research work. The study protocol was also approved by the Institutional Review Board of all institutes involved in the study.
- Cho YG, Choi BJ, Song JH, Kim CJ, Cao Z, Nam SW, Lee JY, Park WS (2008) No association of MDM2 T309G polymorphism with susceptibility to Korean GC patients. Neoplasma 55:256–260Google Scholar
- Choudhury JH, Singh SA, Kundu S, Choudhury B, Talukdar FR, Srivasta S et al (2015) Tobacco carcinogen-metabolizing genes CYP1A1, GSTM1, and GSTT1 polymorphisms and their interaction with tobacco exposure influence the risk of head and neck cancer in northeast Indian population. TumorBiol 36(8):5773–5783Google Scholar
- Ciccarelli C, Marampon F, Scoglio A, Mauro A, Giacinti C, Cesaris PD (2005) P21WAF1 expression induced by MEK/ERK pathway activation or inhibition correlates with growth arrest, myogenic differentiation and onco-phenotype reversal in rhabdomyosarcoma cells. Mol Cancer 13(4):14Google Scholar
- Correa P, Fontham E, Pickle LW, Chen V, Lin YP, Haenszel W (1985) Dietary determinants of GC in south Louisiana inhabitants. J Natl Cancer Inst 75:645–654Google Scholar
- Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, et al. (eds) (2007) Cancer incidence in five continents, vol. IX, IARC Scientific Publications No. 160. IARC, LyonGoogle Scholar
- Ghatak S, Muthukumaran RB, Nachimuthu SK (2013) A simple method of genomic DNA extraction from human samples for PCR-RFLP analysis. J Biomol Tech 24:224–231Google Scholar
- Hedley DW (1994) DNA analysis from paraffin-embedded blocks. Flow cytometry Second Edition, Part A PP: 231–240Google Scholar
- Ihsan R, Devi TR, Yadav DS, Mishra AK, Sharma J, Zomawia E (2011) Investigation on the role of p53 codon 72 polymorphism and interactions with tobacco, betel quid, and alcohol in susceptibility to cancers in a high-risk population from north east India. DNA Cell Biol 30:163–171CrossRefGoogle Scholar
- Keshava C, Frye BL, Wolff MS, McCanlies EC, Weston A (2002) Waf-1 (P21) and p53 polymorphisms in breast cancer. Cancer Epidemiol Biomark Prev 11:127–130Google Scholar
- Kneller RW, Guo WD, Hsing AW, Chen JS, Blot WJ, Li JY et al (1992) Risk factors for stomach cancer in sixty-five Chinese counties. Cancer Epidemiol Biomark Prev 1:113–118Google Scholar
- Kondo E, Suzuki H, Horii A, Fukushige S (2003) A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations. Cancer Res 63:3302–3308Google Scholar
- Malumbres M, Carnero A (2003) Cell cycle deregulation: a common motif in cancer. Prog Cell Cycle Res 5:5–18Google Scholar
- National Cancer Registry Programme (2013) Three-year report of the population based cancer registries 2011–2013. National cancer registry programme, Indian Council of Medical Research (ICMR), Bangalore, India. Available from, http://www.pbcrin-dia.org. Accessed 16 Oct 2014
- Nomura A, Grove JS, Stemmermann GN, Severson RK et al (1990) A prospective study of stomach cancer and its relation to diet, cigarettes, and alcohol consumption. Cancer Res 50:627–631Google Scholar
- Phukan RK, Hazarika NC, Baruah D, Mahanta J (2004) High prevalence of stomach cancer among the people of Mizoram, India. Curr Sci 87:285–286Google Scholar
- Piazuelo MB, Correa P (2013) Gastric cáncer: overview. Colomb Med (Cali) 44(3):192–201Google Scholar
- Raevaara TE, Korhonen MK, Lohi H, Hampel H, Lynch E, Lönnqvist KE (2005) Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology 129:537–549Google Scholar
- Shiohara M, Deiry WE, Wada M, Nakamaki T, Takeuchi S, Yang R (1994) Absence of WAF1 mutations in a variety of human malignancies. Nature 84:3781–3784Google Scholar
- Sumathi B, Ramalingam S, Navaneethan U, Jayanthi V (2009) Risk factors for GC in South India. Singap Med J 50:147–151Google Scholar
- Yan L, Fang L, Sha Z, Suqing S, Li L, Lifeng L (2015) Genetics and GC susceptibility. Int J Clin Exp Med 8(6):8377–8383Google Scholar