Effect of TERT promoter mutation and TERT mRNA expression on prognosis of HCC patients after radical resection surgery_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

GONG Chen ^1,2 , WANG Haiqing ¹ ,  FENG Xielin ¹ , LIU Aixiang ¹ , ZHANG Lixia ¹ , LI Lei ¹ , BO Wentao ¹ , HU Yong ¹ , ZHANG Mingyi ¹ , ZHANG Hui ¹ , TIAN Lang ¹ , TANG Xiaoli ¹

1. Department of Hepatobiliary Surgery, The Affiliated Cancer Hospital, University of Electronic Science and Technology of China, Chengdu 610041, P. R. China;
2. Medical School, University of Electronic Science and Technology of China, Chengdu 610041, P. R. China;

Corresponding author：

FENG Xielin, Email: fengxielinszl@163.com

Keywords：

hepatocellular carcinoma; telomerase reverse transcriptase; prognosis

DOI：

10.7507/1007-9424.201911030

Video：

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Objective To investigate the effects of telomerase reverse transcriptase (TERT) promoter mutation and TERT mRNA expression on the prognosis of patients with hepatocellular carcinoma (HCC) after radical resection, and the clinicopathological factors affecting the prognosis of patients with HCC after radical resection were explored.Methods Clinical data of 212 HCC patients underwent radical resection from Jan. 2009 to Jan. 2016 in The Affiliated Cancer Hospital of University of Electronic Science and Technology of China were selected and analyzed. The mutations of TERT, TP53, and catenin beta 1 (CTNNB1) were detected by Sanger sequencing, and the expression of TERT mRNA was detected by SYBR. Patients were followed up routinely and their overall survival (OS) and disease-free survival (DFS) were recorded.Results The mutation rates of the TERT promoter, TP53, and CTNNB1 gene were 17.9% (38/212), 40.1% (85/212), and 13.7% (29/212), respectively. The TERT promoter mutation had significant correlation with Child-Pugh classification and preoperative albumin value (P<0.05). Expression level of TERT mRNA had significant correlation with HBV infection, Child-Pugh classification, preoperative AST value and ALT value (P<0.05). Cox proportional hazards regression result showed that anatomical hepatectomy, tumor diameter>5 cm, and high expression of TERT mRNA were significant prognostic factors of OS (P<0.05); preoperative platelets count≤100×10⁹/L, tumor diameter>5 cm, and high expression of TERT mRNA were significant prognostic factors of DFS (P<0.05).Conclusion For patients after HCC surgery, high expression of TERT mRNA may be a key factor affecting the prognosis of HCC patients.

Citation： GONG Chen, WANG Haiqing, FENG Xielin, LIU Aixiang, ZHANG Lixia, LI Lei, BO Wentao, HU Yong, ZHANG Mingyi, ZHANG Hui, TIAN Lang, TANG Xiaoli. Effect of TERT promoter mutation and TERT mRNA expression on prognosis of HCC patients after radical resection surgery. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(8): 950-958. doi: 10.7507/1007-9424.201911030 Copy

1.	Yegin EG, Oymaci E, Karatay E, et al. Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment. Hepatobiliary Pancreat Dis Int, 2016, 15(3): 234-256.
2.	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3.	Wang H, Liu A, Bo W, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis. Dig Liver Dis, 2016, 48(11): 1275-1282.
4.	Günes C, Rudolph KL. The role of telomeres in stem cells and cancer. Cell, 2013, 152(3): 390-393.
5.	Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet, 2005, 6(8): 611-622.
6.	Pinyol R, Tovar V, Llovet JM. TERT promoter mutations: gatekeeper and driver of hepatocellular carcinoma. J Hepatol, 2014, 61(3): 685-687.
7.	Li L, Wang H, Yang J, et al. Immediate postoperative low platelet counts after living donor liver transplantation predict early allograft dysfunction. Medicine (Baltimore), 2015, 94(34): e1373.
8.	Fang Q, Xie QS, Chen JM, et al. Long-term outcomes after hepatectomy of huge hepatocellular carcinoma: a single-center experience in China. Hepatobiliary Pancreat Dis Int, 2019, 18(6): 532-537.
9.	Torrecilla S, Sia D, Harrington AN, et al. Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J Hepatol, 2017, 67(6): 1222-1231.
10.	Nault JC, Mallet M, Pilati C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun, 2013, 4: 2218.
11.	Yang X, Guo X, Chen Y, et al. Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma. Oncotarget, 2016, 7(19): 27838-27847.
12.	Pezzuto F, Buonaguro L, Buonaguro FM, et al. Frequency and geographic distribution of TERT promoter mutations in primary hepatocellular carcinoma. Infect Agent Cancer, 2017, 12: 27.
13.	Sung WK, Zheng H, Li S, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet, 2012, 44(7): 765-769.
14.	Kawai-Kitahata F, Asahina Y, Tanaka S, et al. Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. J Gastroenterol, 2016, 51(5): 473-486.
15.	Totoki Y, Tatsuno K, Covington KR, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet, 2014, 46(12): 1267-1273.
16.	Nahon P, Nault JC. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int, 2017, 37(11): 1591-1601.
17.	Chiba K, Lorbeer FK, Shain AH, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science, 2017, 357(6358): 1416-1420.
18.	Nault JC, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol, 2016, 40(1): 9-14.
19.	Sato Y, Yamamoto S, Oya H, et al. Preoperative human-telomerase reverse transcriptase mRNA in peripheral blood and tumor recurrence in living-related liver transplantation for hepatocellular carcinoma. Hepatogastroenterology, 2005, 52(65): 1325-1328.
20.	Oya H, Sato Y, Yamamoto S, et al. Comparison between human-telomerase reverse transcriptase mRNA and alpha-fetoprotein mRNA as a predictive value for recurrence of hepatocellular carcinoma in living donor liver transplantation. Transplant Proc, 2006, 38(10): 3636-3639.
21.	Huang DS, Wang Z, He XJ, et al. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer, 2015, 51(8): 969-976.
22.	Zhang B, Chen J, Cheng AS, et al. Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells. PLoS One, 2014, 9(1): e84931.
23.	Ko E, Seo HW, Jung ES, et al. The TERT promoter SNP rs2853669 decreases E2F1 transcription factor binding and increases mortality and recurrence risks in liver cancer. Oncotarget, 2016, 7(1): 684-699.
24.	Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology, 2012, 56(2): 769-775.
25.	Li L, Li B, Zhang M. HBV DNA levels impact the prognosis of hepatocellular carcinoma patients with microvascular invasion. Medicine (Baltimore), 2019, 98(27): e16308.
26.	Kang KJ, Ahn KS. Anatomical resection of hepatocellular carcinoma: a critical review of the procedure and its benefits on survival. World J Gastroenterol, 2017, 23(7): 1139-1146.
27.	Liu L, Wang Z, Jiang S, et al. Perioperative allogenenic blood transfusion is associated with worse clinical outcomes for hepatocellular carcinoma: a meta-analysis. PLoS One, 2013, 8(5): e64261.
28.	Wang HQ, Yang J, Yang JY, et al. Low immediate postoperative platelet count is associated with hepatic insufficiency after hepatectomy. World J Gastroenterol, 2014, 20(33): 11871-11877.
29.	Gu J, Zhang X, Wang Z, et al. Simplified nomograms based on platelet-associated models for survival prediction in Asian hepatocellular carcinoma patients after surgery. Surg Oncol, 2019, 30: 131-138.
30.	Sitia G, Iannacone M, Guidotti LG. Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma. J Hepatol, 2013, 59(5): 1135-1138.

1. Yegin EG, Oymaci E, Karatay E, et al. Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment. Hepatobiliary Pancreat Dis Int, 2016, 15(3): 234-256.
2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3. Wang H, Liu A, Bo W, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis. Dig Liver Dis, 2016, 48(11): 1275-1282.
4. Günes C, Rudolph KL. The role of telomeres in stem cells and cancer. Cell, 2013, 152(3): 390-393.
5. Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet, 2005, 6(8): 611-622.
6. Pinyol R, Tovar V, Llovet JM. TERT promoter mutations: gatekeeper and driver of hepatocellular carcinoma. J Hepatol, 2014, 61(3): 685-687.
7. Li L, Wang H, Yang J, et al. Immediate postoperative low platelet counts after living donor liver transplantation predict early allograft dysfunction. Medicine (Baltimore), 2015, 94(34): e1373.
8. Fang Q, Xie QS, Chen JM, et al. Long-term outcomes after hepatectomy of huge hepatocellular carcinoma: a single-center experience in China. Hepatobiliary Pancreat Dis Int, 2019, 18(6): 532-537.
9. Torrecilla S, Sia D, Harrington AN, et al. Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J Hepatol, 2017, 67(6): 1222-1231.
10. Nault JC, Mallet M, Pilati C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun, 2013, 4: 2218.
11. Yang X, Guo X, Chen Y, et al. Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma. Oncotarget, 2016, 7(19): 27838-27847.
12. Pezzuto F, Buonaguro L, Buonaguro FM, et al. Frequency and geographic distribution of TERT promoter mutations in primary hepatocellular carcinoma. Infect Agent Cancer, 2017, 12: 27.
13. Sung WK, Zheng H, Li S, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet, 2012, 44(7): 765-769.
14. Kawai-Kitahata F, Asahina Y, Tanaka S, et al. Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. J Gastroenterol, 2016, 51(5): 473-486.
15. Totoki Y, Tatsuno K, Covington KR, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet, 2014, 46(12): 1267-1273.
16. Nahon P, Nault JC. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int, 2017, 37(11): 1591-1601.
17. Chiba K, Lorbeer FK, Shain AH, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science, 2017, 357(6358): 1416-1420.
18. Nault JC, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol, 2016, 40(1): 9-14.
19. Sato Y, Yamamoto S, Oya H, et al. Preoperative human-telomerase reverse transcriptase mRNA in peripheral blood and tumor recurrence in living-related liver transplantation for hepatocellular carcinoma. Hepatogastroenterology, 2005, 52(65): 1325-1328.
20. Oya H, Sato Y, Yamamoto S, et al. Comparison between human-telomerase reverse transcriptase mRNA and alpha-fetoprotein mRNA as a predictive value for recurrence of hepatocellular carcinoma in living donor liver transplantation. Transplant Proc, 2006, 38(10): 3636-3639.
21. Huang DS, Wang Z, He XJ, et al. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer, 2015, 51(8): 969-976.
22. Zhang B, Chen J, Cheng AS, et al. Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells. PLoS One, 2014, 9(1): e84931.
23. Ko E, Seo HW, Jung ES, et al. The TERT promoter SNP rs2853669 decreases E2F1 transcription factor binding and increases mortality and recurrence risks in liver cancer. Oncotarget, 2016, 7(1): 684-699.
24. Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology, 2012, 56(2): 769-775.
25. Li L, Li B, Zhang M. HBV DNA levels impact the prognosis of hepatocellular carcinoma patients with microvascular invasion. Medicine (Baltimore), 2019, 98(27): e16308.
26. Kang KJ, Ahn KS. Anatomical resection of hepatocellular carcinoma: a critical review of the procedure and its benefits on survival. World J Gastroenterol, 2017, 23(7): 1139-1146.
27. Liu L, Wang Z, Jiang S, et al. Perioperative allogenenic blood transfusion is associated with worse clinical outcomes for hepatocellular carcinoma: a meta-analysis. PLoS One, 2013, 8(5): e64261.
28. Wang HQ, Yang J, Yang JY, et al. Low immediate postoperative platelet count is associated with hepatic insufficiency after hepatectomy. World J Gastroenterol, 2014, 20(33): 11871-11877.
29. Gu J, Zhang X, Wang Z, et al. Simplified nomograms based on platelet-associated models for survival prediction in Asian hepatocellular carcinoma patients after surgery. Surg Oncol, 2019, 30: 131-138.
30. Sitia G, Iannacone M, Guidotti LG. Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma. J Hepatol, 2013, 59(5): 1135-1138.

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CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effect of TERT promoter mutation and TERT mRNA expression on prognosis of HCC patients after radical resection surgery

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