A multi‐omic study reveals BTG2 as a reliable prognostic marker for early‐stage non‐small cell lung cancer

B‐cell translocation gene 2 (BTG2) is a tumour suppressor protein known to be downregulated in several types of cancer. In this study, we investigated a potential role for BTG2 in early‐stage non‐small cell lung cancer (NSCLC) survival. We analysed BTG2 methylation data from 1230 early‐stage NSCLC patients from five international cohorts, as well as gene expression data from 3038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumour tissues were associated with lower overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51–2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 expression was positively correlated with survival in each cohort (HR range, 0.28–0.68), which we confirmed with meta‐analysis (HR = 0.61, 95% CI 0.54–0.68). The three CpG probes were all negatively correlated with BTG2 expression. Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set. In conclusion, the methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early‐stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.

[1]  M. Diehn,et al.  Development and Validation of an Individualized Immune Prognostic Signature in Early-Stage Nonsquamous Non–Small Cell Lung Cancer , 2017, JAMA oncology.

[2]  Yang Zhao,et al.  Seven-CpG-based prognostic signature coupled with gene expression predicts survival of oral squamous cell carcinoma , 2017, Clinical Epigenetics.

[3]  M. Reth,et al.  The BTG2-PRMT1 module limits pre-B cell expansion by regulating the CDK4-Cyclin-D3 complex , 2017, Nature Immunology.

[4]  Walter J Curran,et al.  Lung cancer: current therapies and new targeted treatments , 2017, The Lancet.

[5]  Peter A. Jones,et al.  Targeting the cancer epigenome for therapy , 2016, Nature Reviews Genetics.

[6]  S. Lam,et al.  ITPKA Gene Body Methylation Regulates Gene Expression and Serves as an Early Diagnostic Marker in Lung and Other Cancers , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[7]  Kimberly Walter,et al.  Quantitative comparison of DNA methylation assays for biomarker development and clinical applications , 2016, Nature Biotechnology.

[8]  R. Salgia,et al.  Prognostic and Predictive Value in KRAS in Non-Small-Cell Lung Cancer: A Review. , 2016, JAMA oncology.

[9]  B. Séraphin,et al.  BTG2 bridges PABPC1 RNA-binding domains and CAF1 deadenylase to control cell proliferation , 2019 .

[10]  Vessela Kristensen,et al.  Genome‐wide DNA methylation analyses in lung adenocarcinomas: Association with EGFR, KRAS and TP53 mutation status, gene expression and prognosis , 2015, Molecular oncology.

[11]  Wen-Xue Jiang,et al.  BTG2 inhibits the proliferation and metastasis of osteosarcoma cells by suppressing the PI3K/AKT pathway. , 2015, International journal of clinical and experimental pathology.

[12]  David Petersen,et al.  An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[13]  Francesca M Buffa,et al.  Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT. , 2015, The Journal of clinical investigation.

[14]  Kwok-Kin Wong,et al.  Non-small-cell lung cancers: a heterogeneous set of diseases , 2014, Nature Reviews Cancer.

[15]  Brandon D Gallas,et al.  Comparing two correlated C indices with right‐censored survival outcome: a one‐shot nonparametric approach , 2015, Statistics in medicine.

[16]  B. Xiao,et al.  miR-25 modulates NSCLC cell radio-sensitivity through directly inhibiting BTG2 expression. , 2015, Biochemical and biophysical research communications.

[17]  Gangning Liang,et al.  Gene body methylation can alter gene expression and is a therapeutic target in cancer. , 2014, Cancer cell.

[18]  Johan Staaf,et al.  Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome , 2014, Clinical Cancer Research.

[19]  Igor Jurisica,et al.  Validation of a Histology-Independent Prognostic Gene Signature for Early-Stage, Non–Small-Cell Lung Cancer Including Stage IA Patients , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[20]  E. Giovannetti,et al.  MicroRNAs cooperatively inhibit a network of tumor suppressor genes to promote pancreatic tumor growth and progression. , 2014, Gastroenterology.

[21]  Y. Choi,et al.  TIS21(/BTG2/PC3) inhibits interleukin-6 expression via downregulation of STAT3 pathway. , 2013, Cellular signalling.

[22]  I. Lim,et al.  Regulation of Btg2(/TIS21/PC3) expression via reactive oxygen species-protein kinase C-ΝFκΒ pathway under stress conditions. , 2013, Cellular signalling.

[23]  M. Esteller,et al.  A prognostic DNA methylation signature for stage I non-small-cell lung cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  G. Muto,et al.  BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial–mesenchymal transition , 2013, Oncogene.

[25]  J. Li,et al.  BTG2 inhibits the proliferation, invasion, and apoptosis of MDA-MB-231 triple-negative breast cancer cells , 2013, Tumor Biology.

[26]  F. Hoppe-Seyler,et al.  Endogenous BTG2 expression stimulates migration of bladder cancer cells and correlates with poor clinical prognosis for bladder cancer patients , 2013, British Journal of Cancer.

[27]  Jinming Yu,et al.  BTG2 overexpression increases the radiosensitivity of breast cancer cells in vitro and in vivo. , 2012, Oncology research.

[28]  G. Zeng,et al.  Expression and significance of miRNA-21 and BTG2 in lung cancer , 2013, Tumor Biology.

[29]  Peter A. Jones.  Functions of DNA methylation: islands, start sites, gene bodies and beyond , 2012, Nature Reviews Genetics.

[30]  Qinghua Zhou,et al.  Effects of BTG2 on proliferation inhibition and anti-invasion in human lung cancer cells , 2012, Tumor Biology.

[31]  Fang Zhou,et al.  A 5-MicroRNA Signature for Lung Squamous Cell Carcinoma Diagnosis and hsa-miR-31 for Prognosis , 2011, Clinical Cancer Research.

[32]  S. Ramaswamy,et al.  Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib , 2011, Oncogene.

[33]  D. Beer,et al.  MicroRNA classifiers for predicting prognosis of squamous cell lung cancer. , 2009, Cancer research.

[34]  Min Liu,et al.  Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma , 2009, Cell Research.

[35]  Madeleine P. Ball,et al.  Corrigendum: Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells , 2009, Nature Biotechnology.

[36]  Igor Jurisica,et al.  Gene expression–based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study , 2008, Nature Medicine.

[37]  F. Tirone,et al.  Btg2 Enhances Retinoic Acid-Induced Differentiation by Modulating Histone H4 Methylation and Acetylation , 2006, Molecular and Cellular Biology.

[38]  I. Lim,et al.  TIS21/BTG2/PC3 as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule , 2006, Journal of Cancer Research and Clinical Oncology.

[39]  B. Williams,et al.  A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation. , 2006, Genes & development.

[40]  Holger Moch,et al.  Impaired Expression of the Cell Cycle Regulator BTG2 Is Common in Clear Cell Renal Cell Carcinoma , 2004, Cancer Research.

[41]  J. Melamed,et al.  Expression of B-cell translocation gene 2 protein in normal human tissues. , 2002, Tissue & cell.

[42]  F. Tirone,et al.  Cloning of PC3B, a novel member of the PC3/BTG/TOB family of growth inhibitory genes, highly expressed in the olfactory epithelium. , 2000, Genomics.

[43]  V. Sukhatme,et al.  A novel early growth response gene rapidly induced by fibroblast, epithelial cell and lymphocyte mitogens. , 1987, Oncogene research.