title: Multiplatform-based molecular subtypes of non-small-cell lung cancer.
abstract: Non-small-cell lung cancer (NSCLC) demonstrates remarkable molecular diversity. With the completion of The Cancer Genome Atlas (TCGA), there is opportunity for systematic analyses of the entire TCGA NSCLC cohort, including comparisons and contrasts between different disease subsets. On the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy, and RNA and protein expression), 1023 NSCLC cases-519 from TCGA adenocarcinoma (AD) project and 504 from TCGA squamous cell carcinoma (SQCC) project-were classified using a 'cluster-of-clusters' analytic approach. Patterns from TCGA NSCLC subsets were examined in independent external databases, including the PROSPECT (Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax) NSCLC data set. Nine genomic subtypes of NSCLC were identified, three within SQCC and six within AD. SQCC subtypes were associated with transcriptional targets of SOX2 or p63. One predominately AD subtype (with a large proportion of SQCC) shared molecular features with neuroendocrine tumors. Two AD subtypes manifested a CpG island methylator phenotype. Three AD subtypes showed high p38 and mTOR pathway activation. AD subtypes associated with low differentiation showed relatively worse prognosis. SQCC subtypes and two of the AD subtypes expressed cancer testis antigen genes, whereas three AD subtypes expressed several immune checkpoint genes including PDL1 and PDL2, corresponding with patterns of greater immune cell infiltration. Subtype associations for several immune-related markers-including PD1, PDL1, CD3 and CD8-were confirmed in the PROSPECT cohort using immunohistochemistry. NSCLC molecular subtypes have therapeutic implications and lend support to a personalized approach to NSCLC management based on molecular characterization.
authors: Dan L. Duncan Comprehensive Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA.
authors: F
authors: F
authors: Chen
authors: Dan L. Duncan Comprehensive Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA.
authors: Y
authors: Y
authors: Zhang
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, TX, USA.
authors: E
authors: E
authors: Parra
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, TX, USA.
authors: J
authors: J
authors: Rodriguez
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, TX, USA.
authors: C
authors: C
authors: Behrens
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: R
authors: R
authors: Akbani
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Y
authors: Y
authors: Lu
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: J M
authors: JM
authors: Kurie
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: D L
authors: DL
authors: Gibbons
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: G B
authors: GB
authors: Mills
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, TX, USA.|Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: I I
authors: II
authors: Wistuba
authors: Dan L. Duncan Comprehensive Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA.|Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors: C J
authors: CJ
authors: Creighton
mesh_terms: D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000235:genetics*; D019175:DNA Methylation; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases