BRAF in Lung Cancers: Analysis of Patient Cases Reveals Recurrent BRAF Mutations, Fusions, Kinase Duplications, and Concurrent Alterations
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Published:2018-11
Issue:2
Volume:
Page:1-15
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ISSN:2473-4284
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Container-title:JCO Precision Oncology
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language:en
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Short-container-title:JCO Precision Oncology
Author:
Sheikine Yuri1, Pavlick Dean1, Klempner Samuel J.1, Trabucco Sally E.1, Chung Jon H.1, Rosenzweig Mark1, Wang Kai1, Velcheti Vamsidhar1, Frampton Garrett M.1, Peled Nir1, Murray Molly1, Chae Young Kwang1, Albacker Lee A.1, Gay Laurie1, Husain Hatim1, Suh James H.1, Millis Sherri Z.1, Reddy Venkataprasanth P.1, Elvin Julia A.1, Hartmaier Ryan J.1, Dowlati Afshin1, Stephens Phil1, Ross Jeffrey S.1, Bivona Trever G.1, Miller Vincent A.1, Ganesan Shridar1, Schrock Alexa B.1, Ou Sai-Hong Ignatius1, Ali Siraj M.1
Affiliation:
1. Yuri Sheikine, Vancouver General Hospital, Vancouver, British Columbia, Canada; Dean Pavlick, Sally E. Trabucco, Jon H. Chung, Mark Rosenzweig, Kai Wang, Garrett M. Frampton, Molly Murray, Lee A. Albacker, Laurie Gay, James H. Suh, Sherri Z. Millis, Venkataprasanth P. Reddy, Julia A. Elvin, Ryan J. Hartmaier, Phil Stephens, Jeffrey S. Ross, Vincent A. Miller, Alexa B. Schrock, and Siraj M. Ali, Foundation Medicine, Cambridge, MA; Samuel J. Klempner, The Angeles Clinic and Research Institute and Cedars...
Abstract
Purpose Dabrafenib and trametinib are approved for the management of advanced non–small-cell lung cancers (NSCLCs) that harbor BRAF V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 B RAF alterations in lung cancer. Patients and Methods A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic BRAF base substitutions, short insertions and deletions, copy number changes, and rearrangements. Results Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. BRAF was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were BRAF V600E, 38% were BRAF non-V600E activating mutations, and 18% were BRAF inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and BRAF fusions (2.8%). The fusions involved three recurrent fusion partners: ARMC10, DOCK4, and TRIM24. BRAF V600E was associated with co-occurrence of SETD2 alterations, but other BRAF alterations were not and were instead associated with CDKN2A, TP53, and STK11 alterations ( P < .05). Potential mechanisms of acquired resistance to BRAF V600E inhibition are demonstrated. Conclusion This series characterized the frequent occurrence (4.4%) of BRAF alterations in lung cancers. Recurrent BRAF alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as ALK, and exceed that of ROS1 or RET. This work supports a broad profiling approach in lung cancers and suggests that non-V600E BR AF alterations represent a subgroup of lung cancers in which targeted therapy should be considered.
Publisher
American Society of Clinical Oncology (ASCO)
Subject
Cancer Research,Oncology
Cited by
33 articles.
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