Impact of CCL4 gene polymorphisms and environmental factors on oral cancer development and clinical characteristics

// Ming-Yu Lien 1, 2 , Chiao-Wen Lin 3, 4 , Hsiao-Chi Tsai 1 , Yng-Tay Chen 5 , Ming-Hsui Tsai 6 , Chun-Hung Hua 7 , Shun-Fa Yang 8, 9 and Chih-Hsin Tang 1, 10 1 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 2 Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan 3 Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan 4 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan 5 Department of Pediatrics, Medical Research and Medical Genetics, China Medical College Hospital, Taichung, Taiwan 6 Department of Otolaryngology, China Medical University Hospital, Taichung, Taiwan 7 Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan 8 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan 9 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan 10 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan Correspondence to: Chih-Hsin Tang, email: chtang@mail.cmu.edu.tw Shun-Fa Yang, email: ysf@csmu.edu.tw Keywords: oral cancer, CCL4, single-nucleotide polymorphism Received: October 20, 2016      Accepted: January 22, 2017      Published: February 22, 2017 ABSTRACT In Taiwan, oral cancer has causally been associated with environmental carcinogens. CCL4 (C-C chemokine ligand 4), a macrophage inflammatory protein with a key role in inflammation and immune-regulation, was implicated in carcinogenesis by facilitating instability in the tumor environment. The purpose of this study was to identify gene polymorphisms of CCL4 specific to patients with oral squamous cell carcinoma (OSCC) susceptibility and clinicopathological characteristics. A total of 2,053 participants, including 1192 healthy people and 861 patients with oral cancer, were recruited for this study. Three single-nucleotide polymorphisms (SNPs) of the CCL4 gene were analyzed by a real-time PCR. We found that the T/T homozygotes of CCL4 rs1634507 G/T polymorphism and the GG haplotype of 2 CCL4 SNPs (rs1634507 and rs10491121) combined were associated with oral-cancer susceptibility. In addition, TA haplotype significantly decreased the risks for oral cancer by 0.118 fold. Among 1420 smokers, CCL4 polymorphisms carriers with the betel-nut chewing habit had a 15.476–20.247-fold greater risk of having oral cancer compared to CCL4 wild-type (WT) carriers without the betel-nut chewing habit. Finally, patients with oral cancer who had A/G heterozygotes of CCL4 rs10491121 A/G polymorphism showed a lower risk for an advanced tumor size (> T2) ( p =0.046), compared to those patients with AA homozygotes. Our results suggest that the CCL4 rs1634507 SNP have potential predictive significance in oral carcinogenesis. Gene-environment interactions of CCL4 polymorphisms might influence oral-cancer susceptibility. CCL4 rs10491121 may be a factor to predict the tumor size in OSCC patients.