Case Control Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 14, 2015; 21(46): 13064-13072
Published online Dec 14, 2015. doi: 10.3748/wjg.v21.i46.13064
Association between hepatocellular carcinoma and tumor necrosis factor alpha polymorphisms in South Korea
Suk Pyo Shin, Nam Keun Kim, Ju Hwan Kim, Ju Ho Lee, Jung Oh Kim, Sung Hwan Cho, Hana Park, Mi Na Kim, Kyu Sung Rim, Seong Gyu Hwang
Suk Pyo Shin, Ju Hwan Kim, Ju Ho Lee, Hana Park, Kyu Sung Rim, Seong Gyu Hwang, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 463-712, South Korea
Nam Keun Kim, Jung Oh Kim, Sung Hwan Cho, Department of Biomedical Science, College of Life Science, CHA University, Seongnam 463-400, South Korea
Nam Keun Kim, Jung Oh Kim, Sung Hwan Cho, Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam 463-712, South Korea
Suk Pyo Shin, Ju Hwan Kim, Ju Ho Lee, Hana Park, Kyu Sung Rim, Seong Gyu Hwang, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam 463-712, South Korea
Mi Na Kim, Department of Internal Medicine, CHA Gangnam Medical Center, CHA University, Seoul 135-913, South Korea
Author contributions: Shin SP and Kim NK contributed equally to this manuscript and considered as co-first author; Shin SP, Hwang SG and Kim NK designed research; Hwang SG and Rim KS contributed to acquisition of data; Shin SP, Kim NK, Kim JO and Cho SH performed research; Kim JH, Lee JH, Park H and Kim MN analyzed and interpreted data; and Shin SP wrote the manuscript.
Supported by Basic Science Research Program through National Research Foundation of Korea Grants funded by the Korean Government, No. NRF-2012R1A1A2007033 and No. 2009-0093821, South Korea.
Institutional review board statement: The present study was approved by the Institutional Review Board of CHA Bundang Medical Center, and written informed consent was obtained from all case and control subjects in the study.
Conflict-of-interest statement: The authors disclose no conflicts of interest.
Data sharing statement: All the dataset are available from the author at nkkim@cha.ac.kr
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Seong Gyu Hwang, MD, PhD, Professor, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Yatapro 59, Bundang-gu, Seongnam 463-712, South Korea. sghwang@cha.ac.kr
Telephone: +82-31-7805213 Fax: +82-31-7805219
Received: June 29, 2015
Peer-review started: July 4, 2015
First decision: July 19, 2015
Revised: August 24, 2015
Accepted: October 17, 2015
Article in press: October 20, 2015
Published online: December 14, 2015
Processing time: 162 Days and 19.7 Hours
Abstract

AIM: To investigate associations between the tumor necrosis factor alpha (TNF-α) -1031 T>C, -863 C>A, -857 C>T, -308 G>A, and -238 G>A polymorphisms and HCC in Korea.

METHODS: Hepatocellular carcinoma (HCC) cases were diagnosed at CHA Bundang Medical Center from June 1996 to August 2008. The association between TNF-α polymorphisms and HCC was analyzed in 157 HCC patients and 201 controls using a polymerase chain reaction-restriction fragment length polymorphism assay. We investigated five TNF-α polymorphisms, which are TNF-α -1031 T>C, -863 C>A, -857 C>T, -308 G>A, and -238 G>A. The TNF-α genotype frequencies, genotype combinations and haplotypes were analyzed to disclose the association with HCC.

RESULTS: None of the TNF-α polymorphisms was significantly associated with HCC. However, nine genotype combinations had associations with increased likelihood of HCC. Among them, TNF-α -1031/-857/-238 TT/CC/GA (AOR = 18.849, 95%CI: 2.203-161.246, P = 0.007), TNF-α -1031/-308/-238 TT/GG/GA (AOR = 26.956, 95%CI: 3.071-236.584, P = 0.003), and TNF-α -1031/-238 TT/GA (AOR = 21.576, 95%CI: 2.581-180.394, P = 0.005) showed marked association with HCC. There were five haplotypes of TNF-α polymorphisms which were significantly associated with HCC. They are TNF-α -1031/-863/-857/-308/-238 T-C-C-G-A (OR = 25.824, 95%CI: 1.491-447.223, P = 0.0005), TNF-α -1031/-857/-308/-238 T-C-G-A (OR = 12.059, 95%CI: 2.747-52.950, P < 0.0001), TNF-α -1031/-857/-238 T-C-A (OR = 10.696, 95%CI: 2.428-47.110, P = 0.0001), TNF-α -1031/-308/-238 T-G-A (OR = 7.556, 95%CI: 2.173-26.280, P = 0.0002) and TNF-α -1031/-238 T-A (OR = 10.865, 95%CI: 2.473-47.740, P = 0.0001). Moreover, HCC Okuda stage III cases with the TNF-α -1031 CC genotype had better survival than those with the TT genotype (AOR = 5.795, 95%CI: 1.145-29.323).

CONCLUSION: Although no single TNF-α polymorphism is associated with HCC in this study, some TNF-α genotype combinations and haplotypes are associated with HCC. In addition, HCC Okuda stage III cases with the TNF-α -1031 TT genotype may have a better prognosis than those with the CC genotype.

Keywords: Tumor necrosis factor-alpha; Polymorphism; Single nucleotide; Carcinoma; Hepatocellular

Core tip: We genotyped five single nucleotide polymorphisms [Tumor necrosis factor alpha (TNF-α) -1031T>C, -863C>A, -857C>T, -308G>A, and -238G>A] in hepatocellular carcinoma (HCC) patients and control subjects. A number of genotype combinations and some haplotypes had association with HCC. In addition, HCC Okuda stage III cases with the TNF-α -1031 TT genotype had a better prognosis than those with the CC genotype.