Abstract
Targeting rare variants of a pan-cancer target: The landscape of BRAF non-v600 mutations and BRAF fusions from 172,005 adult patients with cancer.
Author
person
Niamh Coleman
Trinity St. James's Cancer Institute, Dublin, Ireland
info_outline
Niamh Coleman, Vivek Subbiah
Full text
Authors
person
Niamh Coleman
Trinity St. James's Cancer Institute, Dublin, Ireland
info_outline
Niamh Coleman, Vivek Subbiah
Organizations
Trinity St. James's Cancer Institute, Dublin, Ireland, Sarah Cannon Research Institute, Nashville, TN
Abstract Disclosures
Research Funding
No funding sources reported
Background:
BRAF is a recognized pan-cancer target, with dabrafenib in combination with trametinib receiving FDA accelerated approval for unresectable metastatic solid tumors with
BRAF
V600E mutation.
BRAF
fusions and mutations at codons aside from V600 (non-V600) activate the MAP kinase/ERK-signaling pathway, however the spectrum of these alterations is not yet well-defined. Preclinical data suggests that
BRAF
non-v600 mutations are diverse, with evidence of alternate signaling, requiring dimerization to function, while
BRAF
V600E tumors activate the pathway as monomers. We include a comprehensive analysis of non-
BRAF
V600 mutations and
BRAF
fusions in pan-cancer adult malignancies.
Methods:
198,041 samples from 172,005 patients available from AACR Project GENIE v.15 (1) database were analyzed for the prevalence of non-V600 BRAF mutations, fusions and copy number alterations in a range of cancer types.
Results:
A total of 6374 separate non-V600
BRAF
alterations were identified in 5876 samples (2.97%), including 1176 fusions (18.4%), 4435 missense mutations (69.6%), 299 truncating mutations (4.7%), and 245 in-frame mutations (3.8%), splice variants (3.4%). Most frequent tumors included lung (19%), melanoma (14%), colorectal (9.7%) glioma (5%), thyroid (1.4%).
BRAF
fusions were observed in 0.7% of tumor samples, most identified in glioma, prostate, lung, thyroid, and colorectal cancer (20%, 7.3%, 6.1%; 4%, 4% of identified
BRAF
fusions, respectively). Most
fusions were considered driver events (1123, 95.5%); frequent fusion gene partners included
KIAA1549
, intragenic fusions,
SND1
,
AGK
,
MKRN1
(39.9%, 15%, 4%, 3.3%, 2.4% of 1176 samples respectively). Of 4435 missense mutations identified, most were considered driver events (2734, 62%); 1701 missense mutations were variants of uncertain significance (VUS) using OncoKB database (38%). Missense mutations occurred across codons, most frequently involving codon 469 (n=584, 13.2%, G469A/V/R/E/S/L/K/I), 466 (n=310, 10.5%, G466V/E/A/R), 594 (n=506, 11.4%, D594G/N/A/E/H/Y/V/F), 601 (n=279, 6.3%, K601E/N/I/T/_S602delinsNT), 581 (n=231, 5.2%, N581S/I/Y/H/T/D/K) 597 (n=118; 2.7%, L597R/Q/S/V/P/H/I).
BRAF
amplification occurred in 0.14% of samples.
Conclusions:
While
BRAF
fusions are rare events across cancers, non-v600
BRAF
alterations occur in 3% of malignancies. Atypical non-V600
BRAF
alterations and BRAF fusions represent a distinct molecular cohort across cancers. Most
BRAF
fusion events and non-V600 missense mutations are characterized as oncogenic, underlining the spectrum of BRAF inhibition, and the urgent need to expand agents beyond the current
BRAF
V600 indications. Functional characterization of atypical
BRAF
variants is therefore crucial, together with enrolling patients with these rare alterations on rationally designed clinical trials. 1. Cancer Discov. 2017.
1 organization
Organization
Trinity St. James's Cancer Institute