Establishment and evaluation of risk prediction model for the esophageal cancer via whole transcriptome analysis_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

FENG Yangbo ¹ , XIONG Yanlu ¹ , ZHAO Jinbo ¹ , LEI Jie ¹ , XIN Shaowei ² , QIAO Tianyun ¹ , ZHOU Yongsheng ¹ , ZHANG Xiao ³ , JIANG Tao ¹ ,  HAN Yong ^1,4

1. Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi’an, 710038, P. R. China;
2. Department of Thoracic Surgery, The 962nd Hospital of the PLA Joint Logistic Support Force, Harbin, 150000, P. R. China;
3. Department of Biochemistry and Molecular Biology, Basic Medical Science Academy, Air Force Medical University, Xi’an, 710038,P. R. China;
4. Department of Thoracic Surgery, Air Force Medical Center, PLA, Beijing, 100142, P. R. China;

Corresponding author：

HAN Yong, Email: hanyong_td@163.com

Keywords：

Esophageal cancer; esophageal squamous cell carcinoma; esophageal adenocarcinoma; prognosis; risk score

DOI：

10.7507/1007-4848.202102010

Video：

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Objective To establish the gene-based esophageal cancer (ESCA) risk score prediction models via whole transcriptome analysis to provide ideas and basis for improving ESCA treatment strategies and patient prognosis.Methods RNA sequencing data of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC) and adjacent tissues were obtained from The Cancer Genome Atlas database. The edgeR method was used to screen out the differential genes between ESCA tissue and normal tissue, and the key genes affecting the survival status of ESCC and EAC patients were initially identified through univariate Cox regression analysis. The least absolute shrinkage and selection operator regression analysis and multivariate Cox regression analysis were used to further screen genes and establish ESCC and EAC risk score prediction models.Results The risk score prediction models were the independent prognostic factors for ESCA, and the risk score was significantly related to the survival status of patients. In ESCC, the risk score was related to T stage. In EAC, the risk score was related to lymph node metastasis, distant metastasis and clinical stage. The constructed nomogram based on risk score showed good predictive ability. In ESCC, the risk score was related to tumor immune cell infiltration and the expression of immune checkpoint genes. However, this feature was not obvious in EAC.Conclusion The ESCC and EAC risk score prediction models have shown good predictive capabilities, which provide certain inspiration and basis for optimizing the management of ESCA and improving the prognosis of patients.

Citation： FENG Yangbo, XIONG Yanlu, ZHAO Jinbo, LEI Jie, XIN Shaowei, QIAO Tianyun, ZHOU Yongsheng, ZHANG Xiao, JIANG Tao, HAN Yong. Establishment and evaluation of risk prediction model for the esophageal cancer via whole transcriptome analysis. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2023, 30(4): 576-585. doi: 10.7507/1007-4848.202102010 Copy

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6.	Shah MA, Kennedy EB, Catenacci DV, et al. Treatment of locally advanced esophageal carcinoma: ASCO guideline. J Clin Oncol, 2020, 38(23): 2677-2694.
7.	Jain S, Dhingra S. Pathology of esophageal cancer and Barrett’s esophagus. Ann Cardiothorac Surg, 2017, 6(2): 99-109.
8.	Engel LS, Chow WH, Vaughan TL, et al. Population attributable risks of esophageal and gastric cancers. J Natl Cancer Inst, 2003, 95(18): 1404-1413.
9.	Chau I, Norman AR, Cunningham D, et al. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer-pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol, 2004, 22(12): 2395-2403.
10.	Gavin AT, Francisci S, Foschi R, et al. Oesophageal cancer survival in Europe: A EUROCARE-4 study. Cancer Epidemiol, 2012, 36(6): 505-512.
11.	Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell, 2011, 144(5): 646-674.
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13.	Barsouk A, Rawla P, Hadjinicolaou AV, et al. Targeted therapies and immunotherapies in the treatment of esophageal cancers. Med Sci (Basel), 2019, 7(10): 100.
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16.	Han B, Zhang YY, Xu K, et al. NUDCD1 promotes metastasis through inducing EMT and inhibiting apoptosis in colorectal cancer. Am J Cancer Res, 2018, 8(5): 810-823.
17.	Rao W, Li H, Song F, et al. OVA66 increases cell growth, invasion and survival via regulation of IGF-1R-MAPK signaling in human cancer cells. Carcinogenesis, 2014, 35(7): 1573-1581.
18.	Boyault S, Rickman DS, de Reyniès A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology, 2007, 45(1): 42-52.
19.	Holzer K, Ori A, Cooke A, et al. Nucleoporin Nup155 is part of the p53 network in liver cancer. Nat Commun, 2019, 10(1): 2147.
20.	He W, Chen L, Yuan K, et al. Gene set enrichment analysis and meta-analysis to identify six key genes regulating and controlling the prognosis of esophageal squamous cell carcinoma. J Thorac Dis, 2018, 10(10): 5714-5726.
21.	Watson NF, Ramage JM, Madjd Z, et al. Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC classⅠexpression correlates with a poor prognosis. Int J Cancer, 2006, 118(1): 6-10.
22.	Umemoto Y, Okano S, Matsumoto Y, et al. Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen classⅠ-positive hepatocellular carcinoma after curative hepatectomy. J Gastroenterol, 2015, 50(1): 65-75.
23.	Mizukami Y, Kono K, Maruyama T, et al. Downregulation of HLA classⅠmolecules in the tumour is associated with a poor prognosis in patients with oesophageal squamous cell carcinoma. Br J Cancer, 2008, 99(9): 1462-1467.
24.	Ljunggren HG, Kärre K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today, 1990, 11(7): 237-244.
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27.	Ito S, Okano S, Morita M, et al. Expression of PD-L1 and HLA classⅠin esophageal squamous cell carcinoma: Prognostic factors for patient outcome. Ann Surg Oncol, 2016, 23(Suppl 4): 508-515.
28.	Jiang YZ, Li QH, Zhao JQ, et al. Identification of a novel fusion gene (HLA-E and HLA-B) by RNA-seq analysis in esophageal squamous cell carcinoma. Asian Pac J Cancer Prev, 2014, 15(5): 2309-2312.
29.	Lee HN, Ahn SM, Jang HH. Cold-inducible RNA-binding protein, CIRP, inhibits DNA damage-induced apoptosis by regulating p53. Biochem Biophys Res Commun, 2015, 464(3): 916-921.
30.	Yang R, Weber DJ, Carrier F. Post-transcriptional regulation of thioredoxin by the stress inducible heterogenous ribonucleoprotein A18. Nucleic Acids Res, 2006, 34(4): 1224-1236.
31.	Biade S, Marinucci M, Schick J, et al. Gene expression profiling of human ovarian tumours. Br J Cancer, 2006, 95(8): 1092-1100.
32.	Guo X, Wu Y, Hartley RS. Cold-inducible RNA-binding protein contributes to human antigen R and cyclin E1 deregulation in breast cancer. Mol Carcinog, 2010, 49(2): 130-140.
33.	Chang ET, Parekh PR, Yang Q, et al. Heterogenous ribonucleoprotein A18 (hnRNP A18) promotes tumor growth by increasing protein translation of selected transcripts in cancer cells. Oncotarget, 2016, 7(9): 10578-10593.
34.	Lujan DA, Ochoa JL, Hartley RS. Cold-inducible RNA binding protein in cancer and inflammation. Wiley Interdiscip Rev RNA, 2018, 9(2): 10.1002/wrna. 1462.
35.	Lee HN, Ahn SM, Jang HH. Cold-inducible RNA-binding protein promotes epithelial-mesenchymal transition by activating ERK and p38 pathways. Biochem Biophys Res Commun, 2016, 477(4): 1038-1044.
36.	Chang MH, Plata C, Zandi-Nejad K, et al. Slc26a9-anion exchanger, channel and Na+ transporter. J Membr Biol, 2009, 228(3): 125-140.
37.	Dorwart MR, Shcheynikov N, Wang Y, et al. SLC26A9 is a Cl(-) channel regulated by the WNK kinases. J Physiol, 2007, 584(Pt 1): 333-345.
38.	Gorbatenko A, Olesen CW, Boedtkjer E, et al. Regulation and roles of bicarbonate transporters in cancer. Front Physiol, 2014, 5: 130.
39.	Seifert M, Reichrath J. The role of the human DNA mismatch repair gene hMSH2 in DNA repair, cell cycle control and apoptosis: implications for pathogenesis, progression and therapy of cancer. J Mol Histol, 2006, 37(5-7): 301-307.
40.	Lynch PM. The hMSH2 and hMLH1 genes in hereditary nonpolyposis colorectal cancer. Surg Oncol Clin N Am, 2009, 18(4): 611-624.
41.	Falkenback D, Johansson J, Halvarsson B, et al. Defective mismatch-repair as a minor tumorigenic pathway in Barrett esophagus-associated adenocarcinoma. Cancer Genet Cytogenet, 2005, 157(1): 82-86.
42.	Evans SC, Gillis A, Geldenhuys L, et al. Microsatellite instability in esophageal adenocarcinoma. Cancer Lett, 2004, 212(2): 241-251.
43.	Xie W, Zhang J, Zhong P, et al. Expression and potential prognostic value of histone family gene signature in breast cancer. Exp Ther Med, 2019, 18(6): 4893-4903.
44.	Hassan M, Alaoui A, Feyen O, et al. The BH3-only member Noxa causes apoptosis in melanoma cells by multiple pathways. Oncogene, 2008, 27(33): 4557-4568.
45.	Liu YL, Lai F, Wilmott JS, et al. Noxa upregulation by oncogenic activation of MEK/ERK through CREB promotes autophagy in human melanoma cells. Oncotarget, 2014, 5(22): 11237-11251.
46.	Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov, 2013, 12(11): 847-865.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Pennathur A, Gibson MK, Jobe BA, et al. Oesophageal carcinoma. Lancet, 2013, 381(9864): 400-412.
3. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
4. Chen W, Zheng R, Zeng H, et al. The incidence and mortality of major cancers in China, 2012. Chin J Cancer, 2016, 35(1): 73.
5. D’Journo XB, Thomas PA. Current management of esophageal cancer. J Thorac Dis, 2014, 6 Suppl 2(Suppl 2): S253-S264.
6. Shah MA, Kennedy EB, Catenacci DV, et al. Treatment of locally advanced esophageal carcinoma: ASCO guideline. J Clin Oncol, 2020, 38(23): 2677-2694.
7. Jain S, Dhingra S. Pathology of esophageal cancer and Barrett’s esophagus. Ann Cardiothorac Surg, 2017, 6(2): 99-109.
8. Engel LS, Chow WH, Vaughan TL, et al. Population attributable risks of esophageal and gastric cancers. J Natl Cancer Inst, 2003, 95(18): 1404-1413.
9. Chau I, Norman AR, Cunningham D, et al. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer-pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol, 2004, 22(12): 2395-2403.
10. Gavin AT, Francisci S, Foschi R, et al. Oesophageal cancer survival in Europe: A EUROCARE-4 study. Cancer Epidemiol, 2012, 36(6): 505-512.
11. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell, 2011, 144(5): 646-674.
12. Fatehi Hassanabad A, Chehade R, Breadner D, et al. Esophageal carcinoma: Towards targeted therapies. Cell Oncol (Dordr), 2020, 43(2): 195-209.
13. Barsouk A, Rawla P, Hadjinicolaou AV, et al. Targeted therapies and immunotherapies in the treatment of esophageal cancers. Med Sci (Basel), 2019, 7(10): 100.
14. Roychowdhury S, Chinnaiyan AM. Translating cancer genomes and transcriptomes for precision oncology. CA Cancer J Clin, 2016, 66(1): 75-88.
15. Yan Y, Phan L, Yang F, et al. A novel mechanism of alternative promoter and splicing regulates the epitope generation of tumor antigen CML66-L. J Immunol, 2004, 172(1): 651-660.
16. Han B, Zhang YY, Xu K, et al. NUDCD1 promotes metastasis through inducing EMT and inhibiting apoptosis in colorectal cancer. Am J Cancer Res, 2018, 8(5): 810-823.
17. Rao W, Li H, Song F, et al. OVA66 increases cell growth, invasion and survival via regulation of IGF-1R-MAPK signaling in human cancer cells. Carcinogenesis, 2014, 35(7): 1573-1581.
18. Boyault S, Rickman DS, de Reyniès A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology, 2007, 45(1): 42-52.
19. Holzer K, Ori A, Cooke A, et al. Nucleoporin Nup155 is part of the p53 network in liver cancer. Nat Commun, 2019, 10(1): 2147.
20. He W, Chen L, Yuan K, et al. Gene set enrichment analysis and meta-analysis to identify six key genes regulating and controlling the prognosis of esophageal squamous cell carcinoma. J Thorac Dis, 2018, 10(10): 5714-5726.
21. Watson NF, Ramage JM, Madjd Z, et al. Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC classⅠexpression correlates with a poor prognosis. Int J Cancer, 2006, 118(1): 6-10.
22. Umemoto Y, Okano S, Matsumoto Y, et al. Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen classⅠ-positive hepatocellular carcinoma after curative hepatectomy. J Gastroenterol, 2015, 50(1): 65-75.
23. Mizukami Y, Kono K, Maruyama T, et al. Downregulation of HLA classⅠmolecules in the tumour is associated with a poor prognosis in patients with oesophageal squamous cell carcinoma. Br J Cancer, 2008, 99(9): 1462-1467.
24. Ljunggren HG, Kärre K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today, 1990, 11(7): 237-244.
25. Ueda Y, Ishikawa K, Shiraishi N, et al. Clinical significance of HLA classⅠheavy chain expression in patients with gastric cancer. J Surg Oncol, 2008, 97(5): 451-455.
26. Zhang X, Lin A, Zhang JG, et al. Alteration of HLA-F and HLAⅠ antigen expression in the tumor is associated with survival in patients with esophageal squamous cell carcinoma. Int J Cancer, 2013, 132(1): 82-89.
27. Ito S, Okano S, Morita M, et al. Expression of PD-L1 and HLA classⅠin esophageal squamous cell carcinoma: Prognostic factors for patient outcome. Ann Surg Oncol, 2016, 23(Suppl 4): 508-515.
28. Jiang YZ, Li QH, Zhao JQ, et al. Identification of a novel fusion gene (HLA-E and HLA-B) by RNA-seq analysis in esophageal squamous cell carcinoma. Asian Pac J Cancer Prev, 2014, 15(5): 2309-2312.
29. Lee HN, Ahn SM, Jang HH. Cold-inducible RNA-binding protein, CIRP, inhibits DNA damage-induced apoptosis by regulating p53. Biochem Biophys Res Commun, 2015, 464(3): 916-921.
30. Yang R, Weber DJ, Carrier F. Post-transcriptional regulation of thioredoxin by the stress inducible heterogenous ribonucleoprotein A18. Nucleic Acids Res, 2006, 34(4): 1224-1236.
31. Biade S, Marinucci M, Schick J, et al. Gene expression profiling of human ovarian tumours. Br J Cancer, 2006, 95(8): 1092-1100.
32. Guo X, Wu Y, Hartley RS. Cold-inducible RNA-binding protein contributes to human antigen R and cyclin E1 deregulation in breast cancer. Mol Carcinog, 2010, 49(2): 130-140.
33. Chang ET, Parekh PR, Yang Q, et al. Heterogenous ribonucleoprotein A18 (hnRNP A18) promotes tumor growth by increasing protein translation of selected transcripts in cancer cells. Oncotarget, 2016, 7(9): 10578-10593.
34. Lujan DA, Ochoa JL, Hartley RS. Cold-inducible RNA binding protein in cancer and inflammation. Wiley Interdiscip Rev RNA, 2018, 9(2): 10.1002/wrna. 1462.
35. Lee HN, Ahn SM, Jang HH. Cold-inducible RNA-binding protein promotes epithelial-mesenchymal transition by activating ERK and p38 pathways. Biochem Biophys Res Commun, 2016, 477(4): 1038-1044.
36. Chang MH, Plata C, Zandi-Nejad K, et al. Slc26a9-anion exchanger, channel and Na+ transporter. J Membr Biol, 2009, 228(3): 125-140.
37. Dorwart MR, Shcheynikov N, Wang Y, et al. SLC26A9 is a Cl(-) channel regulated by the WNK kinases. J Physiol, 2007, 584(Pt 1): 333-345.
38. Gorbatenko A, Olesen CW, Boedtkjer E, et al. Regulation and roles of bicarbonate transporters in cancer. Front Physiol, 2014, 5: 130.
39. Seifert M, Reichrath J. The role of the human DNA mismatch repair gene hMSH2 in DNA repair, cell cycle control and apoptosis: implications for pathogenesis, progression and therapy of cancer. J Mol Histol, 2006, 37(5-7): 301-307.
40. Lynch PM. The hMSH2 and hMLH1 genes in hereditary nonpolyposis colorectal cancer. Surg Oncol Clin N Am, 2009, 18(4): 611-624.
41. Falkenback D, Johansson J, Halvarsson B, et al. Defective mismatch-repair as a minor tumorigenic pathway in Barrett esophagus-associated adenocarcinoma. Cancer Genet Cytogenet, 2005, 157(1): 82-86.
42. Evans SC, Gillis A, Geldenhuys L, et al. Microsatellite instability in esophageal adenocarcinoma. Cancer Lett, 2004, 212(2): 241-251.
43. Xie W, Zhang J, Zhong P, et al. Expression and potential prognostic value of histone family gene signature in breast cancer. Exp Ther Med, 2019, 18(6): 4893-4903.
44. Hassan M, Alaoui A, Feyen O, et al. The BH3-only member Noxa causes apoptosis in melanoma cells by multiple pathways. Oncogene, 2008, 27(33): 4557-4568.
45. Liu YL, Lai F, Wilmott JS, et al. Noxa upregulation by oncogenic activation of MEK/ERK through CREB promotes autophagy in human melanoma cells. Oncotarget, 2014, 5(22): 11237-11251.
46. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov, 2013, 12(11): 847-865.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Establishment and evaluation of risk prediction model for the esophageal cancer via whole transcriptome analysis

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