Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma
Marcin Imielinski, … , Matthew Meyerson, David P. Carbone
Marcin Imielinski, … , Matthew Meyerson, David P. Carbone
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(4):1582-1586. https://doi.org/10.1172/JCI72763.
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Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma

Abstract

Targeted cancer therapies often induce “outlier” responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner. These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

Authors

Marcin Imielinski, Heidi Greulich, Bethany Kaplan, Luiz Araujo, Joseph Amann, Leora Horn, Joan Schiller, Miguel A. Villalona-Calero, Matthew Meyerson, David P. Carbone

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Figure 2

ARAF mutation found in a sorafenib-responsive lung adenocarcinoma defines a novel Raf family somatic mutation hot spot.

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ARAF mutation found in a sorafenib-responsive lung adenocarcinoma define...
(A) Read alignments in tumor DNA (TD, pink) and normal DNA (ND, green) and tumor RNA (TR, aqua), supporting ARAF S214C somatic mutation call (variant bases: brown, G; green, A; blue, C; red, T) in sorafenib-responder case. (B) Aligned ARAF, RAF1, and BRAF protein domain models overlaid with publicly available ( http://cancergenome.nih.gov/), published (3), and sorafenib-responder somatic mutation data (SR-12), colored by tumor of origin. Red labels denote the putative RAF1/ARAF hot spot. BRAF p.V600E mutations are excluded for simplicity. luad, lung adenocarcinoma; skcm, cutaneous melanoma; coad, colorectal adenocarcinoma; stad, gastric adenocarcinoma; hnsc, head and neck squamous cell carcinoma; kirp, kidney renal papillary cell carcinoma; blca, bladder carcinoma; read, rectal adenocarcinoma; lgg, lower-grade glioma; thca, thyroid carcinoma; ucec, uterine corpus endometrial carcinoma; lusc, lung squamous cell carcinoma; gbm, glioblastoma multiforme; brca, breast adenocarcinoma; prad, prostate adenocarcinoma; cesc, cervical squamous cell carcinoma; kirc:kirp, kidney renal clear cell carcinoma; ov, ovarian carcinoma.