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Nat Genet. 2017 Dec;49(12):1693-1704. doi: 10.1038/ng.3990. Epub 2017 Nov 6.

Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.

Author information

1
Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
2
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
3
The Francis Crick Institute, Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London, UK.
4
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA.
5
Department of Medicine, Division of Medical Oncology, University of Colorado, Denver, Aurora, Colorado, USA.
6
Guardant Health, Inc., Redwood City, California, USA.
7
Driver Inc., San Francisco, California, USA.
8
Clovis Oncology Inc., Boulder, Colorado, USA.
9
University of California Davis Cancer Center, Sacramento, California, USA.
10
Moores Cancer Center, University of California San Diego, San Diego, California, USA.

Abstract

A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.

PMID:
29106415
PMCID:
PMC5709185
DOI:
10.1038/ng.3990
[Indexed for MEDLINE]
Free PMC Article

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