Identification of an Amino Acid Metabolism-Related Gene Signature for Predicting Prognosis in Lung Adenocarcinoma

Abstract: Background Dysregulation of amino acid metabolism (AAM) is an important factor in cancer progression. This study intended to study the prognostic value of AAM-related genes in lung adenocarcinoma (LUAD). Methods: The mRNA expression profiles of LUAD datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied as the training and validation sets. After identifying the differentially expressed AAM-related genes, an AAM-related gene signature (AAMRGS) was constructed and validated. Additionally, we systematically analyzed the differences in immune cell infiltration, biological pathways, immunotherapy response, and drug sensitivity between the two AAMRGS subgroups. Results: The prognosis-related signature was constructed on the grounds of key AAM-related genes. LUAD patients were divided into AAMRGS-high and -low groups. Patients in the two subgroups differed in prognosis, tumor microenvironment (TME), biological pathways, and sensitivity to chemotherapy and immunotherapy. The area under the receiver operating characteristics (ROC) and calibration curves showed good predictive ability for the nomogram. Analysis of immune cell infiltration revealed that the TME of the AAMRGS-low group was in a state of immune activation. Conclusion: We constructed an AAMRGS that could effectively predict prognosis and guide treatment strategies for patients with LUAD.

[1]  Jiajun Du,et al.  Prediction of prognosis, immunogenicity and efficacy of immunotherapy based on glutamine metabolism in lung adenocarcinoma , 2022, Frontiers in Immunology.

[2]  Kongming Wu,et al.  Combination strategies with PD-1/PD-L1 blockade: current advances and future directions , 2022, Molecular cancer.

[3]  N. Hanna,et al.  Advances in systemic therapy for non-small cell lung cancer , 2021, BMJ.

[4]  Ying Cheng,et al.  Genomic signatures define three subtypes of EGFR-mutant stage II–III non-small-cell lung cancer with distinct adjuvant therapy outcomes , 2021, Nature Communications.

[5]  L. Song,et al.  Hypoxia-induced Antizyme inhibitors 2 regulates cisplatin resistance through epithelia-mesenchymal transition pathway in non-small cell lung cancer. , 2021, Pulmonary pharmacology & therapeutics.

[6]  R. Rintoul,et al.  Adenocarcinoma spectrum lesions of the lung: Detection, pathology and treatment strategies. , 2021, Cancer treatment reviews.

[7]  Aykut Özgür,et al.  DNA repair pathways and their roles in drug resistance for lung adenocarcinoma , 2021, Molecular Biology Reports.

[8]  A. Jemal,et al.  Cancer Statistics, 2021 , 2021, CA: a cancer journal for clinicians.

[9]  W. Zou,et al.  Amino Acids and Their Transporters in T Cell Immunity and Cancer Therapy. , 2020, Molecular cell.

[10]  Hui Peng,et al.  MULTIFACETED ROLE OF BRANCHED-CHAIN AMINO ACID METABOLISM IN CANCER , 2020, Oncogene.

[11]  A. Chinnaiyan,et al.  Cancer SLC43A2 alters T cell methionine metabolism and histone methylation , 2020, Nature.

[12]  B. Faubert,et al.  Metabolic reprogramming and cancer progression , 2020, Science.

[13]  Jiyeon Kim,et al.  Amino acids in cancer , 2020, Experimental & Molecular Medicine.

[14]  J. Powell,et al.  Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion , 2019, Science.

[15]  Gregory Riely,et al.  Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer: A Review. , 2019, JAMA.

[16]  Ruo-fan Huang,et al.  PSPH Mediates the Metastasis and Proliferation of Non-small Cell Lung Cancer through MAPK Signaling Pathways , 2019, International journal of biological sciences.

[17]  Roy S. Herbst,et al.  The biology and management of non-small cell lung cancer , 2018, Nature.

[18]  R. Bourgon,et al.  TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells , 2018, Nature.

[19]  K. Takeda,et al.  Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells. , 2017, Cell reports.

[20]  Jun S. Liu,et al.  TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. , 2017, Cancer research.

[21]  Jennifer B Dennison,et al.  Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma , 2017, Journal of the National Cancer Institute.

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

[23]  Pornpimol Charoentong,et al.  Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade , 2016, bioRxiv.

[24]  M. Mann,et al.  L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity , 2016, Cell.

[25]  Zlatko Trajanoski,et al.  Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade , 2016, bioRxiv.

[26]  Mithat Gonen,et al.  Nomograms in oncology: more than meets the eye. , 2015, The Lancet. Oncology.

[27]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[28]  Paul Geeleher,et al.  pRRophetic: An R Package for Prediction of Clinical Chemotherapeutic Response from Tumor Gene Expression Levels , 2014, PloS one.

[29]  Ralph J DeBerardinis,et al.  Glutamine and cancer: cell biology, physiology, and clinical opportunities. , 2013, The Journal of clinical investigation.

[30]  Justin Guinney,et al.  GSVA: gene set variation analysis for microarray and RNA-Seq data , 2013, BMC Bioinformatics.

[31]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[32]  Kuen-Feng Chen,et al.  Functional Characterization of Glycine N-Methyltransferase and Its Interactive Protein DEPDC6/DEPTOR in Hepatocellular Carcinoma , 2012, Molecular medicine.

[33]  C. Gatsonis,et al.  Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening , 2012 .

[34]  K. Frauwirth,et al.  Glutamine Uptake and Metabolism Are Coordinately Regulated by ERK/MAPK during T Lymphocyte Activation , 2010, The Journal of Immunology.

[35]  P. Deloukas,et al.  Signatures of mutation and selection in the cancer genome , 2010, Nature.

[36]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[37]  R. Pirker Chemotherapy remains a cornerstone in the treatment of nonsmall cell lung cancer. , 2019, Current Opinion in Oncology.

[38]  友孝 祖父江 National Lung Screening Trialの概要と評価 , 2012 .

[39]  E. Panosyan,et al.  Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase Formulations , 2005, Clinical pharmacokinetics.