Polymorphisms in the apoptosis-associated genes FAS and FASL and risk of oral cancer and malignant potential of oral premalignant lesions in a Taiwanese population Li-Hsuan Wang 1 , Shuo-Chun Ting 2,3 , Chung-Ho Chen 5 , Chi-Cheng Tsai 4,5 , Oliver Lung 6 , Ta-Chih Liu 1 , Chia-Wen Lee 2 , Yen-Yun Wang 2 , Chin-Ling Tsai 7 , Ying-Chu Lin 4 1 Division of Molecular Diagnosis, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 2 School of Dental Hygiene, Kaohsiung Medical University, Kaohsiung, Taiwan; 3 Department of Clinical Laboratory, Division of Blood Bank, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 4 School of Dentistry, Kaohsiung Medical University, Kaohsiung, Taiwan; 5 Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 6 Lethbridge Laboratory, Canadian Food Inspection Agency, Lethbridge, AB, Canada; 7 Department of Neurology Clinic, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan BACKGROUND: Our aim was to measure the relation- ship of FAS ()1377G>A and )670A>G), FASL ()844C>T) gene variants and risk of oral cancer. METHODS: Polymerase chain reaction-restriction frag- ment length polymorphism (PCR-RFLP) analysis was used to determine the FAS and FASL polymorphisms in 294 oral squamous cell carcinoma (OSCC), 53 oral sub- mucous fibrosis (OSF), and 84 oral leukoplakia (OL) pa- tients, as well as in 333 healthy controls. A standardized questionnaire was applied to collect demographic data, and potential confounding factors. JMP statistical soft- ware was used to analyze the association. RESULTS: FAS and FASL polymorphisms were not correlated with OSCC development or the malignant potential of OL by simple and multivariate logistic regression. However, a two- to fourfold difference in the risks of betel quid chewing, alcohol consumption, and smoking on OSCC development were observed between participants with different FAS polymorphisms. FAS polymorphisms were significantly correlated with the malignant potential of OSF. Multivariate logistic regres- sion analysis indicated that FAS A –1377 -G –670 vs. G –1377 - A –670 haplotype (OR = 2.26, 95% CI = 1.16–4.41) was correlated with the malignant potential of OSF. CONCLUSIONS: We suggest that FAS and FASL poly- morphisms are not significantly correlated with OSCC development or malignant potential of OL. The impact of substance usage on OSCC development could be differ- entiated by FAS polymorphisms. FAS A )1377 -G )670 hap- lotype may play a role in the malignant potential of OSF. J Oral Pathol Med (2010) 39: 121–127 Keyword: FAS; FAS ligand; malignant potential; oral cancer; oral submucous fibrosis Introduction Oral cancer is the sixth most common cancer worldwide, accounting for approximately 4% of all cancers (1). In 2007, mortality caused by oral cancer in Taiwan ranked fourth among males and sixth in the entire population (2). Oral leukoplakia (OL) and oral submucous fibrosis (OSF) are known to have malignant potential (3). However, the molecular biological properties that underlie its malignant potential remain unclear. Resis- tance to programmed cell death or apoptosis is a common characteristic of almost all types of cancer and plays a pivotal role in cancer development (4). The FAS and FAS ligand (FASL) system plays a key role in apoptotic signaling and down-regulation of this path- way may facilitate tumorigenesis (5). Up-regulation of FASL expression and down-regulation of FAS expres- sion on oral cancer cell are thought to facilitate evasion from immune surveillance (6) and suggest that the FAS / FASL system may play an important role in the development of oral squamous cell carcinoma (OSCC). Single nucleotide polymorphisms (SNPs) have been proposed to play an important role in the genetic susceptibility to cancer (7). Many studies have reported that functional SNPs can alter gene expression or Correspondence: Ying-Chu Lin, School of Dentistry, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan. Tel: +886 7 322 9746 ext.12, Fax: 886 7 3210 631, E-mail: chulin@kmu.edu.tw Abbreviations: 95% CI, 95% confidence interval; BQ, betel quid; FASL, FAS ligand; OPL, oral premalignant lesions; OR, odds ratio; OSF, oral submucous fibrosis; OSCC, oral squamous cell carcinoma; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphisms; ROS, reactive oxygen species; SD, standard deviation Accepted for publication November 17, 2009 doi: 10.1111/j.1600-0714.2009.00873.x J Oral Pathol Med (2010) 39: 155–161 ª 2010 John Wiley & Sons A/S Æ All rights reserved interscience.wiley.com/journal/jop Journal of Oral Pathology & Medicine