Development and validation of an oxidative phosphorylation-related gene signature in lung adenocarcinoma
Abstract
Aim: To develop an oxidative phosphorylation (OXPHOS)-related gene signature of lung adenocarcinoma (LUAD). Materials & methods: We split The Cancer Genome Atlas LUAD cohort into a training set and a test set; we used the least absolute shrinkage and selection operator Cox method to structure the OXPHOS-related prognostic signature in the training set and verified in the test set and GSE30219 dataset. Meanwhile, the diagnostic model was constructed using the logistic Cox method. Results: The signature consisted of seven genes (LDHA, CFTR, HSPD1, SNHG3, MAP1LC3C, COX6B2, and TWIST1). LUAD patients were divided into high- and low-risk groups, demonstrating good diagnostic and prognostic capabilities. Conclusion: We developed the first-ever OXPHOS-related signature with both prognostic predictive power and diagnostic efficacy.
References
- 1. . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
- 2. . Cancer statistics, 2020. CA Cancer J. Clin. 70(1), 7–30 (2020).
- 3. Somatic genomics and clinical features of lung adenocarcinoma: a retrospective study. PLoS Med. 13(12), e1002162 (2016).
- 4. . Adjuvant chemotherapy of completely resected early stage non-small cell lung cancer (NSCLC). Transl. Lung Cancer Res. 2(5), 403–410 (2013).
- 5. . Progress and prospects of early detection in lung cancer. Open Biol. 7(9), 170070 (2017).
- 6. Revisions to the TNM staging of lung cancer: rationale, significance, and clinical application. Radiographics 38(2), 374–391 (2018).
- 7. . Oxidative phosphorylation as a potential therapeutic target for cancer therapy. Int. J. Cancer 146(1), 10–17 (2020).
- 8. . Oxidative phosphorylation as an emerging target in cancer therapy. Clin. Cancer Res. 24(11), 2482–2490 (2018).
- 9. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat. Med. 23(10), 1234–1240 (2017).
- 10. . Oxidative phosphorylation: a target for novel therapeutic strategies against ovarian cancer. Cancers 10(9), 337 (2018).
- 11. AIF-regulated oxidative phosphorylation supports lung cancer development. Cell Res. 29(7), 579–591 (2019).
- 12. Biomarkers in lung cancer screening: achievements, promises, and challenges. J. Thorac. Oncol. 14(3), 343–357 (2019).
- 13. . Clinical utility of gene-expression signatures in early stage breast cancer. Nat. Rev. Clin. Oncol. 14(10), 595–610 (2017).
- 14. A long non-coding RNA signature to improve prognosis prediction of gastric cancer. Mol. Cancer 15(1), 60 (2016).
- 15. . The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp. Oncol. 19(1A), A68 (2015).
- 16. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 44(8), e71 (2016).
- 17. . Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30(1), 207–210 (2002).
- 18. . GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics 23(14), 1846–1847 (2007).
- 19. Gene: a gene-centered information resource at NCBI. Nucleic Acids Res. 43(D1), D36–D42 (2015).
- 20. An atlas of human metabolism. Sci. Signal. 13(624), eaaz1482 (2020).
- 21. . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26(1), 139–140 (2010).
- 22. . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. B Methodol. 57(1), 289–300 (1995).
- 23. . ggplot2: Elegant Graphics for Data Analysis (2nd Edition). Springer, Cham, Switzerland (2016).
- 24. . Pheatmap: pretty heatmaps. R package version 61, 617 (2012).
- 25. . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16(5), 284–287 (2012).
- 26. . GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics 31(17), 2912–2914 (2015).
- 27. . Building predictive models in R using the caret package. J. Stat. Softw. 28(5), 1–26 (2008).
- 28. . forestplot: advanced forest plot using ‘grid’graphics. R package version 1(2), 70 (2017).
- 29. . glmnet: lasso and elastic-net regularized generalized linear models. R package version 1(4), (2009). http://CRAN.R-project.org/package=glmnet
- 30. . SurvivalROC: time-dependent ROC curve estimation from censored survival data. Biometrics 56(2), 337–344 (2000).
- 31. . rms: regression modeling strategies. R package version 5(2), (2016). http://CRAN.R-project.org/package=rms
- 32. . Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 28(11), 1747–1756 (2018).
- 33. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 12(1), 77 (2011).
- 34. . KLF3 is a crucial regulator of metastasis by controlling STAT3 expression in lung cancer. Mol. Carcinog. 58(11), 1933–1945 (2019).
- 35. Down-regulation of microRNA-144-3p and its clinical value in non-small cell lung cancer: a comprehensive analysis based on microarray, miRNA-sequencing, and quantitative real-time PCR data. Respir. Res. 20(1), 48 (2019).
- 36. Prognostic and predictive value of a microRNA signature in stage II colon cancer: a microRNA expression analysis. Lancet Oncol. 14(13), 1295–1306 (2013).
- 37. Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis. Lancet Oncol. 13(6), 633–641 (2012).
- 38. . Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma. J. Transl. Med. 17(1), 423 (2019).
- 39. Autophagy-related prognostic signature for breast cancer. Mol. Carcinog. 55(3), 292–299 (2016).
- 40. Development and validation of an immune gene-set based prognostic signature in ovarian cancer. EBioMedicine 40, 318–326 (2019).
- 41. Hypoxic-stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non-small cell lung cancer. FASEB J.
doi:10.1096/fj.201700715 (2018) (Epub ahead of print). - 42. FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer. Mol. Cancer 16(1), 124 (2017).
- 43. p53-inducible DPYSL4 associates with mitochondrial supercomplexes and regulates energy metabolism in adipocytes and cancer cells. Proc. Natl Acad. Sci. U S A 115(33), 8370–8375 (2018).
- 44. . HIF-1 signaling in drug resistance to chemotherapy. Curr. Med. Chem. 21(26), 3021–3028 (2014).
- 45. . Cancer in the crosshairs: targeting cancer metabolism with hyperpolarized carbon-13 MRI technology. NMR Biomed. 32(10), e3937 (2019).
- 46. Identification and validation of stromal immunotype predict survival and benefit from adjuvant chemotherapy in patients with muscle-invasive bladder cancer. Clin. Cancer Res. 24(13), 3069–3078 (2018).
- 47. . Gradient lasso for Cox proportional hazards model. Bioinformatics 25(14), 1775–1781 (2009).
- 48. . Deregulated SLC2A1 promotes tumor cell proliferation and metastasis in gastric cancer. Int. J. Mol. Sci. 16(7), 16144–16157 (2015).
- 49. Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Oncogene 36(27), 3797–3806 (2017).
- 50. Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J. 37(20), e99735 (2018).
- 51. . What role does CFTR play in development, differentiation, regeneration and cancer? Int. J. Mol. Sci. 21(9), 3133 (2020).
- 52. Cystic fibrosis transmembrane conductance regulator gene mutation and lung cancer risk. Lung Cancer 70(1), 14–21 (2010).
- 53. The novel prognostic marker, EHMT2, is involved in cell proliferation via HSPD1 regulation in breast cancer. Int. J. Oncol. 54(1), 65–76 (2019).
- 54. . Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res. 22(1), 90–106 (2012).
- 55. lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/β-catenin signaling. Mol. Cancer 19(1), 9 (2020).
- 56. LncRNA SNHG3 is activated by E2F1 and promotes proliferation and migration of non-small-cell lung cancer cells through activating TGF-β pathway and IL-6/JAK2/STAT3 pathway. J. Cell. Physiol. 235(3), 2891–2900 (2020).