APOBEC mutagenesis and copy number alterations are drivers of proteogenomic tumor evolution and heterogeneity in metastatic thoracic tumors

ABSTRACT: Intratumor mutational heterogeneity has been documented in primary non-small cell lung cancer. Here, we elucidate mechanisms of tumor evolution and heterogeneity in metastatic thoracic tumors (lung adenocarcinoma and thymic carcinoma) using whole-exome and transcriptome sequencing, SNP array for copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of metastases obtained by rapid autopsy. APOBEC-mutagenesis, promoted by increased expression of APOBEC3 region transcripts and associated with a high-risk germline APOBEC3 variant, strongly correlated with mutational tumor heterogeneity. TP53 mutation status was associated with APOBEC hypermutator status. Interferon pathways were enriched in tumors with high APOBEC mutagenesis and IFN- induced expression of APOBEC3B in lung adenocarcinoma cells in culture suggesting a role for the immune microenvironment in the generation of mutational heterogeneity. CNA occurring late in tumor evolution correlated with downstream transcriptomic and proteomic heterogeneity, although global proteomic heterogeneity was significantly greater than transcriptomic and CNA heterogeneity. These results illustrate key mechanisms underlying multi-dimensional heterogeneity in metastatic thoracic tumors.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Liver, Lymph Node, Kidney

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: Udayan Guha  

LAB HEAD: Udayan Guha

PROVIDER: PXD012845 | Pride | 2019-05-07

REPOSITORIES: Pride