Blakely, CM;
Watkins, TBK;
Wu, W;
Gini, B;
Chabon, JJ;
McCoach, CE;
McGranahan, N;
... Bivona, TG; + view all
(2017)
Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.
Nature Genetics
, 49
(12)
pp. 1693-1704.
10.1038/ng.3990.
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Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.pdf - Published Version Download (1MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/ng.3990 |
| Publisher version: | https://doi.org/10.1038/ng.3990 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10064069 |
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