Analysis of genes associated with prognosis of intrahepatic cholangiocarcinoma based on transcriptomics_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HAN Weiguang , JIN Chao , XIN Wei , SU Shuixia ,  WANG Qing

Department of General Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi’an 710038, P. R. China;

Corresponding author：

WANG Qing, Email: wangqing@fmmu.edu.cn

Keywords：

intrahepatic cholangiocarcinoma; differentially expressed gene; prognosis; transcriptomics

DOI：

10.7507/1007-9424.202007062

Video：

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Objective To study the abnormal biological pathways of intrahepatic cholangiocarcinoma (ICC) from the transcriptomics level and identify genes associated with the prognosis of ICC.Methods The differentially expressed genes were screened by t test and fold change method, then KEGG functional enrichment analysis was performed on related genes. The STRING database was applied to construct protein interaction network and find the hub nodes of the network by calculating the degree, betweenness, and closeness of each node. Kaplan-Meier survival analysis was performed using log-rank test to identify prognostic genes related to ICC.Results All of 1 134 differentially expressed genes were overlapped in 3 datasets, which were mainly involved in 15 pathways, including DNA replication, cell cycle, drug metabolism, RNA transport, etc. signaling pathways and amino acid synthesis. According to protein interaction network analysis, TAF1, GRB2, E2F4, HNF4A, MYC, and TP53 genes were hub nodes. As GRB2 and TP53 genes were also the death related genes of ICC, it was found that patients with lower GRB2 gene expression had a better overall survival than those with higher GRB2 gene expression (P=0.040 9), while patients with lower TP53 had a worse overall survival than those with higher TP53 gene expression (P=0.027 3), which were also verified in the TCGA database.Conclusions The abnormal cell metabolism is notably related to the tumorigenesis of ICC. TAF1, GRB2, E2F4, HNF4A, MYC, and TP53 are the key genes in the carcinogenesis and progression of ICC. Expressions of GRB2 and TP53 genes are associated with the prognosis of ICC.

Citation： HAN Weiguang, JIN Chao, XIN Wei, SU Shuixia, WANG Qing. Analysis of genes associated with prognosis of intrahepatic cholangiocarcinoma based on transcriptomics. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(4): 472-476. doi: 10.7507/1007-9424.202007062 Copy

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4.	Zhang H, Yang T, Wu M, et al. Intrahepatic cholangiocarcinoma: Epidemiology, risk factors, diagnosis and surgical management. Cancer Lett, 2016, 379(2): 198-205.
5.	Chun YS, Javle M. Systemic and adjuvant therapies for intrahepatic cholangiocarcinoma. Cancer Control, 2017, 24(3): 1145164505.
6.	Spolverato G, Vitale A, Cucchetti A, et al. Can hepatic resection provide a long-term cure for patients with intrahepatic cholangiocarcinoma? Cancer, 2015, 121(22): 3998-4006.
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9.	Ercolani G, Vetrone G, Grazi GL, et al. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg, 2010, 252(1): 107-114.
10.	Kim YH, Hong EK, Kong SY, et al. Two classes of intrahepatic cholangiocarcinoma defined by relative abundance of mutations and copy number alterations. Oncotarget, 2016, 7(17): 23825-23836.
11.	Zhou D, Gao B, Yang Q, et al. Integrative analysis of ceRNA network reveals functional lncRNAs in intrahepatic cholangiocarcinoma. Biomed Res Int, 2019, 2019: 2601271.
12.	Liu ZH, Lian BF, Dong QZ, et al. Whole-exome mutational and transcriptional landscapes of combined hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma reveal molecular diversity. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(6 Pt B): 2360-2368.
13.	Jain A, Javle M. Molecular profiling of biliary tract cancer: a target rich disease. J Gastrointest Oncol, 2016, 7(5): 797-803.
14.	Jain A, Kwong L N, Javle M. Genomic profiling of biliary tract cancers and implications for clinical practice. Curr Treat Options Oncol, 2016, 17(11): 58.
15.	Churi CR, Shroff R, Wang Y, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One, 2014, 9(12): e115383.
16.	Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res, 2000, 28(1): 27-30.
17.	von Mering C, Huynen M, Jaeggi D, et al. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res, 2003, 31(1): 258-261.
18.	Yu H, Wang H, Dong W, et al. The diagnostic and prognostic value of UBE2T in intrahepatic cholangiocarcinoma. PeerJ, 2020, 8: e8454.
19.	Sanmai S, Proungvitaya T, Limpaiboon T, et al. Serum pyruvate dehydrogenase kinase as a prognostic marker for cholangiocarcinoma. Oncol Lett, 2019, 17(6): 5275-5282.
20.	Meng LQ. Essential role of polymorphism of Gab1, EGFR, and EGF for the susceptibility of biliary tract cancer. Tumour Biol, 2014, 35(12): 12497-12508.
21.	Iwaki J, Kikuchi K, Mizuguchi Y, et al. MiR-376c down-regulation accelerates EGF-dependent migration by targeting GRB2 in the HuCCT1 human intrahepatic cholangiocarcinoma cell line. PLoS One, 2013, 8(7): e69496.
22.	Simbolo M, Vicentini C, Ruzzenente A, et al. Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma. Sci Rep, 2018, 8(1): 7119.

1. Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol, 2014, 60(6): 1268-1289.
2. Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer, 2004, 4(9): 695-706.
3. Lee AJ, Chun YS. Intrahepatic cholangiocarcinoma: the AJCC/UICC 8th edition updates. Chin Clin Oncol, 2018, 7(5): 52.
4. Zhang H, Yang T, Wu M, et al. Intrahepatic cholangiocarcinoma: Epidemiology, risk factors, diagnosis and surgical management. Cancer Lett, 2016, 379(2): 198-205.
5. Chun YS, Javle M. Systemic and adjuvant therapies for intrahepatic cholangiocarcinoma. Cancer Control, 2017, 24(3): 1145164505.
6. Spolverato G, Vitale A, Cucchetti A, et al. Can hepatic resection provide a long-term cure for patients with intrahepatic cholangiocarcinoma? Cancer, 2015, 121(22): 3998-4006.
7. Weber SM, Ribero D, O’Reilly EM, et al. Intrahepatic cholangiocarcinoma: expert consensus statement. HPB (Oxford), 2015, 17(8): 669-680.
8. Malka D, Cervera P, Foulon S, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol, 2014, 15(8): 819-828.
9. Ercolani G, Vetrone G, Grazi GL, et al. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg, 2010, 252(1): 107-114.
10. Kim YH, Hong EK, Kong SY, et al. Two classes of intrahepatic cholangiocarcinoma defined by relative abundance of mutations and copy number alterations. Oncotarget, 2016, 7(17): 23825-23836.
11. Zhou D, Gao B, Yang Q, et al. Integrative analysis of ceRNA network reveals functional lncRNAs in intrahepatic cholangiocarcinoma. Biomed Res Int, 2019, 2019: 2601271.
12. Liu ZH, Lian BF, Dong QZ, et al. Whole-exome mutational and transcriptional landscapes of combined hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma reveal molecular diversity. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(6 Pt B): 2360-2368.
13. Jain A, Javle M. Molecular profiling of biliary tract cancer: a target rich disease. J Gastrointest Oncol, 2016, 7(5): 797-803.
14. Jain A, Kwong L N, Javle M. Genomic profiling of biliary tract cancers and implications for clinical practice. Curr Treat Options Oncol, 2016, 17(11): 58.
15. Churi CR, Shroff R, Wang Y, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One, 2014, 9(12): e115383.
16. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res, 2000, 28(1): 27-30.
17. von Mering C, Huynen M, Jaeggi D, et al. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res, 2003, 31(1): 258-261.
18. Yu H, Wang H, Dong W, et al. The diagnostic and prognostic value of UBE2T in intrahepatic cholangiocarcinoma. PeerJ, 2020, 8: e8454.
19. Sanmai S, Proungvitaya T, Limpaiboon T, et al. Serum pyruvate dehydrogenase kinase as a prognostic marker for cholangiocarcinoma. Oncol Lett, 2019, 17(6): 5275-5282.
20. Meng LQ. Essential role of polymorphism of Gab1, EGFR, and EGF for the susceptibility of biliary tract cancer. Tumour Biol, 2014, 35(12): 12497-12508.
21. Iwaki J, Kikuchi K, Mizuguchi Y, et al. MiR-376c down-regulation accelerates EGF-dependent migration by targeting GRB2 in the HuCCT1 human intrahepatic cholangiocarcinoma cell line. PLoS One, 2013, 8(7): e69496.
22. Simbolo M, Vicentini C, Ruzzenente A, et al. Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma. Sci Rep, 2018, 8(1): 7119.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Analysis of genes associated with prognosis of intrahepatic cholangiocarcinoma based on transcriptomics

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