Functional genetic variant in the Kozak sequence of WW domain-containing oxidoreductase (WWOX) gene is associated with oral cancer risk
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Hsin-Lin Cheng1,*, Yu-Fan Liu2,*, Chun-Wen Su1, Shih-Chi Su3, Mu-Kuan Chen1,4, Shun-Fa Yang1,5 and Chiao-Wen Lin6,7
1 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
2 Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
3 Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
4 Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
5 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
6 Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
7 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
* These authors contributed equally to the work.
Chiao-Wen Lin, email:
Keywords: single nucleotide polymorphism, WWOX, oral cancer
Received: August 01, 2016 Accepted: September 10, 2016 Published: September 16, 2016
In Taiwan, oral cancer is the fourth leading cancer in males and is associated with exposure to environmental carcinogens. WW domain-containing oxidoreductase (WWOX), a tumor suppressor gene, is associated with the development of various cancers. We hypothesized that genetic variants of WWOX influence the susceptibility to oral cancer. Five polymorphisms of WWOX gene from 761 male patients with oral cancer and 1199 male cancer-free individuals were genotyped. We observed that individuals carrying the polymorphic allele of WWOX rs11545028 are more susceptible to oral cancer. Furthermore, patients with advanced-stage oral cancer were associated with a higher frequency of WWOX rs11545028 polymorphisms with the variant genotype TT than did patients with the wild-type gene. An additional integrated in silico analysis confirmed that rs11545028 affects WWOX expression, which significantly correlates with tumor expression and subsequently with tumor development and aggressiveness. In conclusion, genetic variants of WWOX contribute to the occurrence of oral cancer, and the findings regarding these biomarkers provided a prediction model for risk assessment.
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