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Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Research

A novel machine learning model based on ubiquitin-related gene pairs and clinical features to predict prognosis and treatment effect in colon adenocarcinoma

Authors: Liping Liang, Le Liu, Shijie Mai, Ye Chen

Published in: European Journal of Medical Research | Issue 1/2023

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Abstract

Background

Ubiquitin and ubiquitin-like (UB/UBL) conjugations are essential post-translational modifications that contribute to cancer onset and advancement. In colon adenocarcinoma (COAD), nonetheless, the biological role, as well as the clinical value of ubiquitin-related genes (URGs), is unclear. The current study sought to design and verify a ubiquitin-related gene pairs (URGPs)-related prognostic signature for predicting COAD prognoses.

Methods

Using univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression, URGP's predictive signature was discovered. Signatures differentiated high-risk and low-risk patients. ROC and Kaplan–Meier assessed URGPs' signature. Gene set enrichment analysis (GSEA) examined biological nomogram enrichment. Chemotherapy and tumor immune microenvironment were also studied.

Results

The predictive signature used six URGPs. High-risk patients had a worse prognosis than low-risk patients, according to Kaplan–Meier. After adjusting for other clinical characteristics, the URGPs signature could reliably predict COAD patients. In the low-risk group, we found higher amounts of invading CD4 memory-activated T cells, follicular helper T cells, macrophages, and resting dendritic cells. Moreover, low-risk group had higher immune checkpoint-related gene expression and chemosensitivity.

Conclusion

Our research developed a nomogram and a URGPs prognostic signature to predict COAD prognosis, which may aid in patient risk stratification and offer an effective evaluation method of individualized treatment in clinical settings.
Appendix
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Literature
1.
go back to reference Kriegsmann M, Longuespee R, Wandernoth P, Mohanu C, Lisenko K, Weichert W, Warth A, Dienemann H, De Pauw E, Katzenberger T, Aust D, Baretton G, Kriegsmann J, Casadonte R. Typing of colon and lung adenocarcinoma by high throughput imaging mass spectrometry. Biochim Biophys Acta Proteins Proteom. 2017;1865:858–64.CrossRef Kriegsmann M, Longuespee R, Wandernoth P, Mohanu C, Lisenko K, Weichert W, Warth A, Dienemann H, De Pauw E, Katzenberger T, Aust D, Baretton G, Kriegsmann J, Casadonte R. Typing of colon and lung adenocarcinoma by high throughput imaging mass spectrometry. Biochim Biophys Acta Proteins Proteom. 2017;1865:858–64.CrossRef
2.
go back to reference Lombardi L, Morelli F, Cinieri S, Santini D, Silvestris N, Fazio N, Orlando L, Tonini G, Colucci G, Maiello E. Adjuvant colon cancer chemotherapy: where we are and where we’ll go. Cancer Treat Rev. 2010;36(Suppl 3):S34-41.CrossRef Lombardi L, Morelli F, Cinieri S, Santini D, Silvestris N, Fazio N, Orlando L, Tonini G, Colucci G, Maiello E. Adjuvant colon cancer chemotherapy: where we are and where we’ll go. Cancer Treat Rev. 2010;36(Suppl 3):S34-41.CrossRef
3.
go back to reference Cass AW, Million RR, Pfaff WW. Patterns of recurrence following surgery alone for adenocarcinoma of the colon and rectum. Cancer AM Cancer Soc. 1976;37:2861–5. Cass AW, Million RR, Pfaff WW. Patterns of recurrence following surgery alone for adenocarcinoma of the colon and rectum. Cancer AM Cancer Soc. 1976;37:2861–5.
4.
go back to reference Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019;16:713–32.CrossRef Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019;16:713–32.CrossRef
5.
go back to reference Kanani A, Veen T, Soreide K. Neoadjuvant immunotherapy in primary and metastatic colorectal cancer. Br J Surg. 2021;108:1417–25.CrossRef Kanani A, Veen T, Soreide K. Neoadjuvant immunotherapy in primary and metastatic colorectal cancer. Br J Surg. 2021;108:1417–25.CrossRef
6.
go back to reference Swatek KN, Komander D. Ubiquitin modifications. Cell Res. 2016;26:399–422.CrossRef Swatek KN, Komander D. Ubiquitin modifications. Cell Res. 2016;26:399–422.CrossRef
7.
go back to reference Pickart CM. Ubiquitin enters the new millennium. Mol Cell. 2001;8:499–504.CrossRef Pickart CM. Ubiquitin enters the new millennium. Mol Cell. 2001;8:499–504.CrossRef
8.
go back to reference Meng Y, Qiu L, Zhang S, Han J. The emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance. Cancer Drug Resist. 2021;4:365–81. Meng Y, Qiu L, Zhang S, Han J. The emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance. Cancer Drug Resist. 2021;4:365–81.
9.
go back to reference Heride C, Urbe S, Clague MJ. Ubiquitin code assembly and disassembly. Curr Biol. 2014;24:R215–20.CrossRef Heride C, Urbe S, Clague MJ. Ubiquitin code assembly and disassembly. Curr Biol. 2014;24:R215–20.CrossRef
10.
go back to reference Park HB, Baek KH. E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers. Biochim Biophys Acta Rev Cancer. 2022;1877: 188736.CrossRef Park HB, Baek KH. E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers. Biochim Biophys Acta Rev Cancer. 2022;1877: 188736.CrossRef
11.
go back to reference Buchberger A. From UBA to UBX: new words in the ubiquitin vocabulary. Trends Cell Biol. 2002;12:216–21.CrossRef Buchberger A. From UBA to UBX: new words in the ubiquitin vocabulary. Trends Cell Biol. 2002;12:216–21.CrossRef
12.
go back to reference Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20:1242–53.CrossRef Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20:1242–53.CrossRef
13.
go back to reference Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008;5:621–8.CrossRef Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008;5:621–8.CrossRef
14.
go back to reference Zhou J, Xu Y, Lin S, Guo Y, Deng W, Zhang Y, Guo A, Xue Y. iUUCD 2.0: an update with rich annotations for ubiquitin and ubiquitin-like conjugations. Nucleic Acids Res. 2018;46:D447–53.CrossRef Zhou J, Xu Y, Lin S, Guo Y, Deng W, Zhang Y, Guo A, Xue Y. iUUCD 2.0: an update with rich annotations for ubiquitin and ubiquitin-like conjugations. Nucleic Acids Res. 2018;46:D447–53.CrossRef
15.
go back to reference Ma Z, Zhong P, Yue P, Sun Z. Uncovering of key pathways and miRNAs for intracranial aneurysm based on weighted gene co-expression network analysis. Eur Neurol. 2022;85:212–23.CrossRef Ma Z, Zhong P, Yue P, Sun Z. Uncovering of key pathways and miRNAs for intracranial aneurysm based on weighted gene co-expression network analysis. Eur Neurol. 2022;85:212–23.CrossRef
16.
go back to reference Cao K, Liu M, Ma K, Jiang X, Ma J, Zhu J. Prediction of prognosis and immunotherapy response with a robust immune-related lncRNA pair signature in lung adenocarcinoma. Cancer Immunol Immunother. 2022;71:1295–311.CrossRef Cao K, Liu M, Ma K, Jiang X, Ma J, Zhu J. Prediction of prognosis and immunotherapy response with a robust immune-related lncRNA pair signature in lung adenocarcinoma. Cancer Immunol Immunother. 2022;71:1295–311.CrossRef
17.
go back to reference Huang CW, Syed-Abdul S, Jian WS, Iqbal U, Nguyen PA, Lee P, Lin SH, Hsu WD, Wu MS, Wang CF, Ma KL, Li YC. A novel tool for visualizing chronic kidney disease associated polymorbidity: a 13-year cohort study in Taiwan. J Am Med Inform Assoc. 2015;22:290–8.CrossRef Huang CW, Syed-Abdul S, Jian WS, Iqbal U, Nguyen PA, Lee P, Lin SH, Hsu WD, Wu MS, Wang CF, Ma KL, Li YC. A novel tool for visualizing chronic kidney disease associated polymorbidity: a 13-year cohort study in Taiwan. J Am Med Inform Assoc. 2015;22:290–8.CrossRef
18.
go back to reference Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.CrossRef Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.CrossRef
19.
go back to reference Kanehisa M, Sato Y, Morishima K. BlastKOALA and GhostKOALA: KEGG tools for functional characterization of genome and metagenome sequences. J Mol Biol. 2016;428:726–31.CrossRef Kanehisa M, Sato Y, Morishima K. BlastKOALA and GhostKOALA: KEGG tools for functional characterization of genome and metagenome sequences. J Mol Biol. 2016;428:726–31.CrossRef
20.
go back to reference Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.CrossRef Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.CrossRef
21.
go back to reference Geeleher P, Cox N, Huang RS. pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS ONE. 2014;9: e107468.CrossRef Geeleher P, Cox N, Huang RS. pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS ONE. 2014;9: e107468.CrossRef
22.
go back to reference Pickart CM, Eddins MJ. Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta. 2004;1695:55–72.CrossRef Pickart CM, Eddins MJ. Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta. 2004;1695:55–72.CrossRef
23.
go back to reference Love IM, Shi D, Grossman SR. p53 Ubiquitination and proteasomal degradation. Methods Mol Biol. 2013;962:63–73.CrossRef Love IM, Shi D, Grossman SR. p53 Ubiquitination and proteasomal degradation. Methods Mol Biol. 2013;962:63–73.CrossRef
24.
go back to reference Li YC, Cai SW, Shu YB, Chen MW, Shi Z. USP15 in cancer and other diseases: from diverse functions to therapeutic targets. Biomedicines. 2022;10:474.CrossRef Li YC, Cai SW, Shu YB, Chen MW, Shi Z. USP15 in cancer and other diseases: from diverse functions to therapeutic targets. Biomedicines. 2022;10:474.CrossRef
25.
go back to reference Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.CrossRef Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.CrossRef
26.
go back to reference Lai G, Zhong X, Liu H, Deng J, Li K, Xie B. Development of a Hallmark pathway-related gene signature associated with immune response for lower grade gliomas. Int J Mol Sci. 2022;23:11971.CrossRef Lai G, Zhong X, Liu H, Deng J, Li K, Xie B. Development of a Hallmark pathway-related gene signature associated with immune response for lower grade gliomas. Int J Mol Sci. 2022;23:11971.CrossRef
27.
go back to reference Lai G, Liu H, Deng J, Li K, Xie B. A novel 3-gene signature for identifying COVID-19 patients based on bioinformatics and machine learning. Genes (Basel). 2022;13:1602.CrossRef Lai G, Liu H, Deng J, Li K, Xie B. A novel 3-gene signature for identifying COVID-19 patients based on bioinformatics and machine learning. Genes (Basel). 2022;13:1602.CrossRef
28.
go back to reference Tibshirani R. The lasso method for variable selection in the Cox model. Stat Med. 1997;16:385–95.CrossRef Tibshirani R. The lasso method for variable selection in the Cox model. Stat Med. 1997;16:385–95.CrossRef
29.
go back to reference Wang W, Liu W. PCLasso: a protein complex-based, group lasso-Cox model for accurate prognosis and risk protein complex discovery. Brief Bioinform. 2021; 22. Wang W, Liu W. PCLasso: a protein complex-based, group lasso-Cox model for accurate prognosis and risk protein complex discovery. Brief Bioinform. 2021; 22.
30.
go back to reference Chen X, Gao K, Xiang Z, Zhang Y, Peng X. Identification and validation of an endoplasmic reticulum stress-related lncRNA signature for colon adenocarcinoma patients. Int J Gen Med. 2022;15:4303–19.CrossRef Chen X, Gao K, Xiang Z, Zhang Y, Peng X. Identification and validation of an endoplasmic reticulum stress-related lncRNA signature for colon adenocarcinoma patients. Int J Gen Med. 2022;15:4303–19.CrossRef
31.
go back to reference Rong H, Li Y, Hu S, Gao L, Yi T, Xie Y, Cai P, Li J, Dai X, Ye M, Liao Q. Prognostic signatures and potential pathogenesis of eRNAs-related genes in colon adenocarcinoma. Mol Carcinog. 2022;61:59–72.CrossRef Rong H, Li Y, Hu S, Gao L, Yi T, Xie Y, Cai P, Li J, Dai X, Ye M, Liao Q. Prognostic signatures and potential pathogenesis of eRNAs-related genes in colon adenocarcinoma. Mol Carcinog. 2022;61:59–72.CrossRef
32.
go back to reference Jiang F, Hu Y, Liu X, Wang M, Wu C. Methylation pattern mediated by m(6)A regulator and tumor microenvironment invasion in lung adenocarcinoma. Oxid Med Cell Longev. 2022;2022:2930310.CrossRef Jiang F, Hu Y, Liu X, Wang M, Wu C. Methylation pattern mediated by m(6)A regulator and tumor microenvironment invasion in lung adenocarcinoma. Oxid Med Cell Longev. 2022;2022:2930310.CrossRef
33.
go back to reference Guo CR, Mao Y, Jiang F, Juan CX, Zhou GP, Li N. Computational detection of a genome instability-derived lncRNA signature for predicting the clinical outcome of lung adenocarcinoma. Cancer Med. 2022;11:864–79.CrossRef Guo CR, Mao Y, Jiang F, Juan CX, Zhou GP, Li N. Computational detection of a genome instability-derived lncRNA signature for predicting the clinical outcome of lung adenocarcinoma. Cancer Med. 2022;11:864–79.CrossRef
34.
go back to reference Yu S, Zang W, Qiu Y, Liao L, Zheng X. Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis. Oncogene. 2022;41:46–56.CrossRef Yu S, Zang W, Qiu Y, Liao L, Zheng X. Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis. Oncogene. 2022;41:46–56.CrossRef
35.
go back to reference Liu X, Xian Y, Xu H, Hu M, Che K, Liu X, Wang H. The associations between Deltex1 and clinical characteristics of breast cancer. Gland Surg. 2021;10:3116–27.CrossRef Liu X, Xian Y, Xu H, Hu M, Che K, Liu X, Wang H. The associations between Deltex1 and clinical characteristics of breast cancer. Gland Surg. 2021;10:3116–27.CrossRef
36.
go back to reference Tang J, Luo Y, Long G, Zhou L. Correction to: MINDY1 promotes breast cancer cell proliferation by stabilizing estrogen receptor alpha. Cell Death Dis. 2022;13:88.CrossRef Tang J, Luo Y, Long G, Zhou L. Correction to: MINDY1 promotes breast cancer cell proliferation by stabilizing estrogen receptor alpha. Cell Death Dis. 2022;13:88.CrossRef
37.
go back to reference Xu X, Xuan X, Zhang J, Xu H, Yang X, Zhang L, Zhao Y, Xu H, Li D. PSMD7 downregulation suppresses lung cancer progression by regulating the p53 pathway. J Cancer. 2021;12:4945–57.CrossRef Xu X, Xuan X, Zhang J, Xu H, Yang X, Zhang L, Zhao Y, Xu H, Li D. PSMD7 downregulation suppresses lung cancer progression by regulating the p53 pathway. J Cancer. 2021;12:4945–57.CrossRef
38.
go back to reference Huang W, Zeng C, Hu S, Wang L, Liu J. ATG3, a target of miR-431-5p, promotes proliferation and invasion of colon cancer via promoting autophagy. Cancer Manag Res. 2019;11:10275–85.CrossRef Huang W, Zeng C, Hu S, Wang L, Liu J. ATG3, a target of miR-431-5p, promotes proliferation and invasion of colon cancer via promoting autophagy. Cancer Manag Res. 2019;11:10275–85.CrossRef
39.
go back to reference Burada F, Ciurea ME, Nicoli R, Streata I, Vilcea ID, Rogoveanu I, Ioana M. ATG16L1 T300A polymorphism is correlated with gastric cancer susceptibility. Pathol Oncol Res. 2016;22:317–22.CrossRef Burada F, Ciurea ME, Nicoli R, Streata I, Vilcea ID, Rogoveanu I, Ioana M. ATG16L1 T300A polymorphism is correlated with gastric cancer susceptibility. Pathol Oncol Res. 2016;22:317–22.CrossRef
40.
go back to reference Xie M, Xin C. RASD2 promotes the development and metastasis of uveal melanoma via enhancing glycolysis. Biochem Biophys Res Commun. 2022;610:92–8.CrossRef Xie M, Xin C. RASD2 promotes the development and metastasis of uveal melanoma via enhancing glycolysis. Biochem Biophys Res Commun. 2022;610:92–8.CrossRef
41.
go back to reference Ro EJ, Cho YH, Jeong WJ, Park JC, Min DS, Choi KY. WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer. Cell Commun Signal. 2019;17:88.CrossRef Ro EJ, Cho YH, Jeong WJ, Park JC, Min DS, Choi KY. WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer. Cell Commun Signal. 2019;17:88.CrossRef
42.
go back to reference Saiyin H, Na N, Han X, Fang Y, Wu Y, Lou W, Yang X. BRSK2 induced by nutrient deprivation promotes Akt activity in pancreatic cancer via downregulation of mTOR activity. Oncotarget. 2017;8:44669–81.CrossRef Saiyin H, Na N, Han X, Fang Y, Wu Y, Lou W, Yang X. BRSK2 induced by nutrient deprivation promotes Akt activity in pancreatic cancer via downregulation of mTOR activity. Oncotarget. 2017;8:44669–81.CrossRef
43.
go back to reference Lin A, Zhang J, Luo P. Crosstalk between the MSI status and tumor microenvironment in colorectal cancer. Front Immunol. 2020;11:2039.CrossRef Lin A, Zhang J, Luo P. Crosstalk between the MSI status and tumor microenvironment in colorectal cancer. Front Immunol. 2020;11:2039.CrossRef
Metadata
Title
A novel machine learning model based on ubiquitin-related gene pairs and clinical features to predict prognosis and treatment effect in colon adenocarcinoma
Authors
Liping Liang
Le Liu
Shijie Mai
Ye Chen
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-00993-z

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