Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity

摘要: Elucidation of the proteogenomic evolution metastatic tumors may offer insight into poor prognosis patients harboring disease. We performed whole-exome and transcriptome sequencing, copy number alterations (CNA) mass spectrometry-based quantitative proteomics 37 lung adenocarcinoma (LUAD) thymic carcinoma (TC) metastases obtained by rapid autopsy found evidence patient-specific, multi-dimensional heterogeneity. Extreme mutational heterogeneity was evident in a subset whose showed increased APOBEC-signature mutations expression APOBEC3 region transcripts compared to with lesser TP53 mutation status associated APOBEC hypermutators our cohort three independent LUAD datasets. In patient, extreme APOBEC3AB high-risk germline variant allele. Patients CNA occurring late tumor had corresponding changes gene protein abundance indicating genomic instability as mechanism downstream transcriptomic proteomic between metastases. Across all tumors, greater than Enrichment interferon pathways both proteome enriched for mutagenesis despite heterogeneous immune microenvironment across suggesting role generation The evolving, nature TC, through APOBEC-mutagenesis illustrate challenges facing treatment outcomes.