Title |
Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers
|
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Published in |
Nature Genetics, November 2017
|
DOI | 10.1038/ng.3990 |
Pubmed ID | |
Authors |
Collin M Blakely, Thomas B K Watkins, Wei Wu, Beatrice Gini, Jacob J Chabon, Caroline E McCoach, Nicholas McGranahan, Gareth A Wilson, Nicolai J Birkbak, Victor R Olivas, Julia Rotow, Ashley Maynard, Victoria Wang, Matthew A Gubens, Kimberly C Banks, Richard B Lanman, Aleah F Caulin, John St John, Anibal R Cordero, Petros Giannikopoulos, Andrew D Simmons, Philip C Mack, David R Gandara, Hatim Husain, Robert C Doebele, Jonathan W Riess, Maximilian Diehn, Charles Swanton, Trever G Bivona |
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. |
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Germany | 4 | 3% |
France | 4 | 3% |
Belgium | 2 | 1% |
Japan | 2 | 1% |
Other | 20 | 13% |
Unknown | 63 | 40% |
Demographic breakdown
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Scientists | 52 | 33% |
Practitioners (doctors, other healthcare professionals) | 22 | 14% |
Science communicators (journalists, bloggers, editors) | 5 | 3% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 298 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 65 | 22% |
Student > Ph. D. Student | 43 | 14% |
Student > Master | 27 | 9% |
Student > Bachelor | 14 | 5% |
Student > Doctoral Student | 13 | 4% |
Other | 45 | 15% |
Unknown | 91 | 31% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 65 | 22% |
Medicine and Dentistry | 60 | 20% |
Agricultural and Biological Sciences | 34 | 11% |
Pharmacology, Toxicology and Pharmaceutical Science | 10 | 3% |
Computer Science | 5 | 2% |
Other | 24 | 8% |
Unknown | 100 | 34% |