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Development of a prognostic metabolic signature in stomach adenocarcinoma

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Abstract

Purpose

The growth and aggressiveness of Stomach adenocarcinoma (STAD) is significantly affected by basic metabolic changes. This study aimed to identify metabolic gene prognostic signatures in STAD.

Methods

An integrative analysis of datasets from the Cancer Genome Atlas and Gene Expression Omnibus was performed. A metabolic gene prognostic signature was developed using univariable Cox regression and Kaplan–Meier survival analysis. A nomogram model was developed to predict the prognosis of STAD patients. Finally, Gene Set Enrichment Analysis (GESA) was used to explore the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways significantly associated with the risk grouping.

Results

A total of 327 metabolism-related differentially expressed genes were identified. Three subtypes of STAD were identified and nine immune cell types, including memory B cell, resting and activated CD4+ memory T cells, were significantly different among the three subgroups. A risk score model including nine survival-related genes which could separate high-risk patients from low-risk patients was developed. The prognosis of STAD patients likely benefited from lower expression levels of genes, including ABCG4, ABCA6, GPX8, KYNU, ST8SIA5, and CYP19A1. Age, radiation therapy, tumor recurrence, and risk score model status were found to be independent risk factors for STAD and were used for developing a nomogram. Nine KEGG pathways, including spliceosome, pentose phosphate pathway, and citrate TCA cycle were significantly enriched in GESA.

Conclusion

We propose a metabolic gene signature and a nomogram for STAD which might be used for predicting the survival of STAD patients and exploring prognostic markers.

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References

  1. Ramazani Y, Mardani E, Najafi F, Moradinazar M, Amini M. Epidemiology of gastric cancer in North Africa and the middle east from 1990 to 2017. J Gastrointest Cancer. 2021;52:1046–53.

    Article  PubMed  Google Scholar 

  2. Yang L, Ying X, Liu S, Lyu G, Xu Z, Zhang X, Li H, Li Q, Wang N, Ji J. Gastric cancer: epidemiology, risk factors and prevention strategies. Chin J Cancer Res. 2020;32:695–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  4. Okugawa Y, Mohri Y, Tanaka K, Kawamura M, Saigusa S, Toiyama Y, Ohi M, Inoue Y, Miki C, Kusunoki M. Metastasis-associated protein is a predictive biomarker for metastasis and recurrence in gastric cancer. Oncol Rep. 2016;36:1893–900.

    Article  CAS  PubMed  Google Scholar 

  5. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11:85–95.

    Article  CAS  PubMed  Google Scholar 

  6. Tabe Y, Lorenzi PL, Konopleva M. Amino acid metabolism in hematologic malignancies and the era of targeted therapy. Blood. 2019;134:1014–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. D’Aniello C, Patriarca EJ, Phang JM, Minchiotti G. Proline Metabolism in Tumor Growth and Metastatic Progression. Front Oncol. 2020;10:776.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Li Z, Zhang H. Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression. Cell Mol Life Sci. 2016;73:377–92.

    Article  CAS  PubMed  Google Scholar 

  9. Glunde K, Jacobs MA, Bhujwalla ZM. Choline metabolism in cancer: implications for diagnosis and therapy. Expert Rev Mol Diagn. 2006;6:821–9.

    Article  CAS  PubMed  Google Scholar 

  10. Dai M, Ma T, Niu Y, Zhang M, Zhu Z, Wang S, Liu H. Analysis of low-molecular-weight metabolites in stomach cancer cells by a simplified and inexpensive GC/MS metabolomics method. Anal Bioanal Chem. 2020;412:2981–91.

    Article  CAS  PubMed  Google Scholar 

  11. Lario S, Ramírez-Lázaro MJ, Sanjuan-Herráez D, Brunet-Vega A, Pericay C, Gombau L, Junquera F, Quintás G, Calvet X. Plasma sample based analysis of gastric cancer progression using targeted metabolomics. Sci Rep. 2017;7:17774.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Chen JL, Tang HQ, Hu JD, Fan J, Hong J, Gu JZ. Metabolomics of gastric cancer metastasis detected by gas chromatography and mass spectrometry. World J Gastroenterol. 2010;16:5874–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Barrett T, Troup DB, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, et al. NCBI GEO: archive for functional genomics data sets–10 years on. Nucleic Acids Res. 2011;39:D1005–10.

    Article  CAS  PubMed  Google Scholar 

  14. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, Liu J, Yue YG, Wang J, Yu K, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56.

    Article  CAS  PubMed  Google Scholar 

  15. Oh SC, Sohn BH, Cheong JH, Kim SB, Lee JE, Park KC, Lee SH, Park JL, Park YY, Lee HS, et al. Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype. Nat Commun. 2018;9:1777.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:47.

    Article  CAS  Google Scholar 

  17. Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA. 1998;95:14863–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang L, Cao C, Ma Q, Zeng Q, Wang H, Cheng Z, Zhu G, Qi J, Ma H, Nian H, et al. RNA-seq analyses of multiple meristems of soybean: novel and alternative transcripts, evolutionary and functional implications. BMC Plant Biol. 2014;14:169.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Huo Y, Li S, Liu J, Li X, Luo XJ. Functional genomics reveal gene regulatory mechanisms underlying schizophrenia risk. Nat Commun. 2019;10:670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.

    Article  CAS  Google Scholar 

  21. da Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37:1–13.

    Article  CAS  Google Scholar 

  22. Zhang X, Ren L, Yan X, Shan Y, Liu L, Zhou J, Kuang Q, Li M, Long H, Lai W. Identification of immune-related lncRNAs in periodontitis reveals regulation network of gene-lncRNA-pathway-immunocyte. Int Immunopharmacol. 2020;84:106600.

    Article  CAS  PubMed  Google Scholar 

  23. Wang P, Wang Y, Hang B, Zou X, Mao JH. A novel gene expression-based prognostic scoring system to predict survival in gastric cancer. Oncotarget. 2016;7:55343–51.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA. Profiling tumor infiltrating immune cells with CIBERSORT. Methods Mol Biol. 2018;1711:243–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tibshirani R. The lasso method for variable selection in the Cox model. Stat Med. 1997;16:385–95.

    Article  CAS  PubMed  Google Scholar 

  27. Goeman JJ. L1 penalized estimation in the Cox proportional hazards model. Biom J. 2010;52:70–84.

    PubMed  Google Scholar 

  28. Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15:361–87.

    Article  PubMed  Google Scholar 

  29. Mayr A, Schmid M. Boosting the concordance index for survival data–a unified framework to derive and evaluate biomarker combinations. PLoS ONE. 2014;9:e84483.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Shan S, Chen W, Jia JD. Transcriptome analysis revealed a highly connected gene module associated with cirrhosis to hepatocellular carcinoma development. Front Genet. 2019;10:305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.

    Article  CAS  PubMed  Google Scholar 

  33. Durinck S, Spellman PT, Birney E, Huber W. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc. 2009;4:1184–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Storch J, Corsico B. The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu Rev Nutr. 2008;28:73–95.

    Article  CAS  PubMed  Google Scholar 

  35. Wilkerson MD, Hayes DN. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010;26:1572–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gong PJ, Shao YC, Huang SR, Zeng YF, Yuan XN, Xu JJ, Yin WN, Wei L, Zhang JW. Hypoxia-associated prognostic markers and competing endogenous RNA co-expression networks in breast cancer. Front Oncol. 2020;10:579868.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Du Y, Ji Z, Liao J, Liu H, Peng H. Identification of molecular subtypes in head and neck squamous cell carcinoma based on dysregulated immune LncRNAs. J Oncol. 2022;2022:9702789.

    PubMed  PubMed Central  Google Scholar 

  38. Li G, Wu Z, Gu J, Zhu Y, Zhang T, Wang F, Huang K, Gu C, Xu K, Zhan R, et al. Metabolic signature-based subtypes may pave novel ways for low-grade glioma prognosis and therapy. Front Cell Dev Biol. 2021;9:755776.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Shen K, Liu T. Comprehensive analysis of the prognostic value and immune function of immune checkpoints in stomach adenocarcinoma. Int J Gen Med. 2021;14:5807–24.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Derks S, de Klerk LK, Xu X, Fleitas T, Liu KX, Liu Y, Dietlein F, Margolis C, Chiaravalli AM, Da Silva AC, et al. Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas. Ann Oncol. 2020;31:1011–20.

    Article  CAS  PubMed  Google Scholar 

  41. Wang X, Hu LP, Qin WT, Yang Q, Chen DY, Li Q, Zhou KX, Huang PQ, Xu CJ, Li J, et al. Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis. Nat Commun. 2021;12:174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tomas L, Edsfeldt A, Mollet IG, Perisic Matic L, Prehn C, Adamski J, Paulsson-Berne G, Hedin U, Nilsson J, Bengtsson E, et al. Altered metabolism distinguishes high-risk from stable carotid atherosclerotic plaques. Eur Heart J. 2018;39:2301–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Robertson AG, Shih J, Yau C, Gibb EA, Oba J, Mungall KL, Hess JM, Uzunangelov V, Walter V, Danilova L, et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell. 2017;32:204-20.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jia Y, Dai J, Zeng Z. Potential relationship between the selenoproteome and cancer. Mol Clin Oncol. 2020;13:83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang R, Zheng Z, Xian S, Zhang J, Jia J, Song D, Yan P, Yin H, Hu P, Zhu X, et al. Identification of prognostic and bone metastatic alternative splicing signatures in bladder cancer. Bioengineered. 2021;12:5289–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wu S, Dai X, Xie D. Identification and validation of an immune-related RNA signature to predict survival of patients with head and neck squamous cell carcinoma. Front Genet. 2019;10:1252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Batcioglu K, Mehmet N, Ozturk IC, Yilmaz M, Aydogdu N, Erguvan R, Uyumlu B, Genc M, Karagozler AA. Lipid peroxidation and antioxidant status in stomach cancer. Cancer Invest. 2006;24:18–21.

    Article  CAS  PubMed  Google Scholar 

  48. Hong C, Yang S, Wang Q, Zhang S, Wu W, Chen J, Zhong D, Li M, Li L, Li J, et al. Epigenetic age acceleration of stomach adenocarcinoma associated with tumor stemness features, immunoactivation, and favorable prognosis. Front Genet. 2021;12:563051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hazard L, O’Connor J, Scaife C. Role of radiation therapy in gastric adenocarcinoma. World J Gastroenterol. 2006;12:1511–20.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Duan S, Wang P, Liu F, Huang H, An W, Pan S, Wang X. Novel immune-risk score of gastric cancer: a molecular prediction model combining the value of immune-risk status and chemosensitivity. Cancer Med. 2019;8:2675–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Polterauer S, Grimm C, Hofstetter G, Concin N, Natter C, Sturdza A, Pötter R, Marth C, Reinthaller A, Heinze G. Nomogram prediction for overall survival of patients diagnosed with cervical cancer. Br J Cancer. 2012;107:918–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Balachandran VP, Gonen M, Smith JJ, DeMatteo RP. Nomograms in oncology: more than meets the eye. Lancet Oncol. 2015;16:e173–80.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by Changzhou Sci&Tech (CJ20200097) and Young Science & Technology Project of Changzhou Health Commission (QN202033).

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Authors

Contributions

YG and SW conceived and designed the study, and drafted the manuscript. SD, SC and GC collected, analyzed and interpreted the experimental data. KB, HY and YJ revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yuwen Jiao.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by Ethical Committee of The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University and conducted in accordance with the ethical standards.

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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Cite this article

Gong, Y., Wu, S., Dong, S. et al. Development of a prognostic metabolic signature in stomach adenocarcinoma. Clin Transl Oncol 24, 1615–1630 (2022). https://doi.org/10.1007/s12094-022-02809-8

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  • DOI: https://doi.org/10.1007/s12094-022-02809-8

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