Multiregion gene expression profiling reveals heterogeneity in molecular subtypes and immunotherapy response signatures in lung cancer

Won Chul Lee, Lixia Diao, Jing Wang, Jianhua Zhang, Emily B. Roarty, Susan Varghese, Chi Wan Chow, Junya Fujimoto, Carmen Behrens, Tina Cascone, Weiyi Peng, Neda Kalhor, Cesar A. Moran, Annikka Weissferdt, Faye M. Johnson, William N. William, Stephen G. Swisher, J. Jack Lee, Waun Ki Hong, John V. HeymachIgnacio I. Wistuba, P. Andrew Futreal, Jianjun Zhang

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Intra-tumor heterogeneity may be present at all molecular levels. Genomic intra-tumor heterogeneity at the exome level has been reported in many cancer types, but comprehensive gene expression intra-tumor heterogeneity has not been well studied. Here, we delineated the gene expression intra-tumor heterogeneity by exploring gene expression profiles of 35 tumor regions from 10 non-small cell lung cancer tumors (three or four regions/tumor), including adenocarcinoma, squamous cell carcinoma, large-cell carcinoma, and pleomorphic carcinoma of the lung. Using Affymetrix Gene 1.0 ST arrays, we generated the gene expression data for every sample. Inter-tumor heterogeneity was generally higher than intra-tumor heterogeneity, but some tumors showed a substantial level of intra-tumor heterogeneity. The analysis of various clinically relevant gene expression signatures including molecular subtype, epithelial-to-mesenchymal transition, and anti-PD-1 resistance signatures also revealed heterogeneity between different regions of the same tumor. The gene expression intra-tumor heterogeneity we observed was associated with heterogeneous tumor microenvironments represented by stromal and immune cells infiltrated. Our data suggest that RNA-based prognostic or predictive molecular tests should be carefully conducted in consideration of the gene expression intra-tumor heterogeneity.

Original languageEnglish (US)
Pages (from-to)947-955
Number of pages9
JournalModern Pathology
Volume31
Issue number6
DOIs
StatePublished - Jun 1 2018

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

MD Anderson CCSG core facilities

  • Bioinformatics Shared Resource
  • Biostatistics Resource Group

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