PT  - JOURNAL ARTICLE
AU  - Nitin Roper
AU  - Shaojian Gao
AU  - Tapan K. Maity
AU  - A. Rouf Banday
AU  - Xu Zhang
AU  - Abhilash Venugopalan
AU  - Constance M. Cultraro
AU  - Rajesh Patidar
AU  - Sivasish Sindiri
AU  - Alexandr Goncearenco
AU  - Anna R. Panchenko
AU  - Romi Biswas
AU  - Anish Thomas
AU  - Arun Rajan
AU  - Corey A. Carter
AU  - David Kleiner
AU  - Stephen Hewitt
AU  - Javed Khan
AU  - Ludmila Prokunina-Olsson
AU  - Udayan Guha
TI  - Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity
AID  - 10.1101/301390
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 301390
4099  - http://biorxiv.org/content/early/2018/04/14/301390.short
4100  - http://biorxiv.org/content/early/2018/04/14/301390.full
AB  - Elucidation of the proteogenomic evolution of metastatic tumors may offer insight into the poor prognosis of patients harboring metastatic disease. We performed whole-exome and transcriptome sequencing, copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of 37 lung adenocarcinoma (LUAD) and thymic carcinoma (TC) metastases obtained by rapid autopsy and found evidence of patient-specific, multi-dimensional heterogeneity. Extreme mutational heterogeneity was evident in a subset of patients whose tumors showed increased APOBEC-signature mutations and expression of APOBEC3 region transcripts compared to patients with lesser mutational heterogeneity. TP53 mutation status was associated with APOBEC hypermutators in our cohort and in three independent LUAD datasets. In a thymic carcinoma patient, extreme heterogeneity and increased APOBEC3AB expression was associated with a high-risk germline APOBEC3AB variant allele. Patients with CNA occurring late in tumor evolution had corresponding changes in gene expression and protein abundance indicating genomic instability as a mechanism of downstream transcriptomic and proteomic heterogeneity between metastases. Across all tumors, proteomic heterogeneity was greater than copy number and transcriptomic heterogeneity. Enrichment of interferon pathways was evident both in the transcriptome and proteome of the tumors enriched for APOBEC mutagenesis despite a heterogeneous immune microenvironment across metastases suggesting a role for the immune microenvironment in the expression of APOBEC transcripts and generation of mutational heterogeneity. The evolving, heterogeneous nature of LUAD and TC, through APOBEC-mutagenesis and CNA illustrate the challenges facing treatment outcomes.