<p>Integrated proteo-genomics studies to characterize tumor heterogeneity of metastatic lung adenocarcinoma and thymic carcinoma are lacking. We carried out whole exome sequencing, RNA sequencing, copy number estimation and mass spectrometry-based proteomics of 40 tumors from five rapid/warm autopsy patients. We found highly variable mutational heterogeneity that was largely driven by APOBEC-mutagenesis with the expression of APOBEC3B (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=APOBEC3B">Gene ID: 9582</a>) and APOBEC3A_B (<a href="https://www.ncbi.nlm.nih.gov/gene/100913187">Gene ID: 100913187</a>) due to underlying APOBEC3 region germline variants as the likely mediating mechanism. APOBEC3A_B expression was associated with increased immune tumor microenvironment and CD274 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=CD274">Gene ID: 29126</a>) expression while smoking was associated with increased APOBEC-mutagenesis in TP53 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=TP53">Gene ID: 7157</a>) mutant tumors with high APOBEC3B expression. Heterogeneity at the level of the transcriptome and proteome occurred in association with copy number heterogeneity, not APOBEC-induced mutational heterogeneity. Arm and focal copy number alterations (CNAs) occurred as an evolutionarily late event in a subset of patients, with corresponding changes in the transcriptome and proteome, implicating CNAs as a driving force of heterogeneity in the evolution of metastatic disease.</p>

Rapid Autopsy in Thoracic Malignancy Cancer Patients to Investigate Tumor Heterogeneity

APOBEC Mutagenesis and Copy-Number Alterations Are Drivers of Proteogenomic Tumor Evolution and Heterogeneity in Metastatic Thoracic Tumors