Integrated Omic Analysis of Lung Cancer Reveals Metabolism Proteome Signatures with Prognostic Impact

Abstract

An Omics Array integrating DNA gene copy number, mRNA transcriptome, and quantified proteome was assembled into a genetic map representing non-small cell lung carcinoma (NSCLC). Data was from patient-matched normal lung, primary tumors, and patient tumor-derived xenograft tumors. Dysregulated proteins not previously implicated as cancer drivers were found encoded throughout the genome including but not limited to regions of recurrent DNA amplification/deletion in NSCLC. Clustering revealed signatures comprising metabolism proteins particularly highly recapitulated between matched primary and PDX tumors. Interrogation of The Cancer Genome Atlas revealed sizeable cohorts of NSCLC patients with DNA alterations in genes encoding the metabolism proteome signatures, and accompanied by differences in survival. Serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in Ser/Gly/folate/1-carbon metabolism, is upregulated in NSCLC proteomes and implicated as a driver of recurrent chromosome 12q14.1 amplification. SHMT2, along with other folate metabolism enzymes is also part of a metabolism signature associated with poor outcome in lung ADC. The interrogation of cancer genomes and proteomes for alterations that are related products of selective pressures driving the cancer phenotype may be a general approach to uncover and group together cryptic, polygenic cancer drivers, which might represent new anti-cancer therapeutic targets.