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BRAF in Lung Cancers: Analysis of Patient Cases Reveals Recurrent BRAF Mutations, Fusions, Kinase Duplications, and

Yuri Sheikine1, Dean Pavlick1, Samuel J Klempner1

  • 1, Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ.

JCO Precision Oncology
|September 11, 2020
PubMed
Abstract

Insights

This study found BRAF alterations in 4.4% of lung cancers, including non-V600E mutations and rearrangements. These findings support comprehensive genomic profiling and suggest targeted therapy for non-V600E BRAF alterations in lung cancer.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Dabrafenib and trametinib target BRAF V600E mutations in non-small-cell lung cancer (NSCLC).
  • Non-V600 alterations are emerging therapeutic targets in various cancers.
  • Comprehensive characterization of non-V600 BRAF alterations in lung cancer is needed.

Purpose of the Study:

  • To comprehensively characterize non-V600 BRAF alterations in a large lung cancer cohort.
  • To identify the frequency and types of BRAF alterations, including mutations and rearrangements.
  • To explore potential therapeutic implications of these findings.

Main Methods:

  • Comprehensive genomic profiling of 23,396 lung cancer patients.
  • Analysis of BRAF base substitutions, insertions/deletions, copy number changes, and rearrangements.
  • Review of data for predicted pathogenic BRAF alterations.

Main Results:

  • BRAF alterations occurred in 4.5% of lung cancers, with 37.4% V600E, 38% non-V600E activating, and 18% inactivating mutations.
  • Rearrangements (4.3%) included N-terminal deletions, kinase domain duplications, and fusions (ARMC10, DOCK4, TRIM24).
  • BRAF V600E co-occurred with SETD2 alterations, while other BRAF alterations associated with CDKN2A, TP53, and STK11.

Conclusions:

  • BRAF alterations are frequent (4.4%) in lung cancers, comparable to ALK and exceeding ROS1/RET in NSCLC adenocarcinoma.
  • Non-V600E BRAF alterations represent a distinct subgroup warranting consideration for targeted therapy.
  • Broad genomic profiling is recommended for lung cancer patients.

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