Abstract PR08: NF1, MET, and RIT1 mutations are RAS-pathway driver events in lung adenocarcinoma
Authors: Berger Alice H. , Brooks Angela N. , Imielinski Marcin , Cherniack Andrew , Duke Fujiko , Kaplan Nathan , Wala Jeremiah , Meyerson Matthew 
Published: May 2015

Abstract
Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic alterations such as EGFR and KRAS mutations. Identification of these oncogenic events has transformed treatment strategies and drug development for lung adenocarcinoma. However, such mutations have been identified in only 50-60% of lung adenocarcinoma cases in the United States.
We analyzed SNP array, exome, and RNA sequencing data from 230 primary lung adenocarcinomas to identify known and novel mutually exclusive driver events. MET exon 14 skipping was present in 10/230 tumors (4.3%) and only RNA sequencing data allowed robust detection of this event. To identify novel driver events, we performed a focused statistical analysis of the 87/230 tumors (38%) that lacked a mutation in MET or other known oncogenes. Copy number analysis revealed rare, focal amplifications of MET and ERBB2 that were enriched in this subset. Exome analysis revealed significant enrichment of TP53, KEAP1, NF1, and RIT1 mutations in the previously oncogene-negative subset. Of these mutated genes, only NF1 and RIT1 displayed mutual exclusivity with the other known and candidate driver events.
Whereas TP53, KEAP1, and NF1 are well-documented cancer genes, little is known about the role of RIT1 in human cancer. RIT1 is a RAS-subfamily small GTPase with significant homology to HRAS, NRAS, and KRAS. Mutations in RIT1 were present in ∼2% of cases and clustered in the switch II domain. Ectopic expression of mutated RIT1 in murine fibroblasts and human immortalized lung epithelial cells conferred anchorage-independent growth and tumor forming capability. cDNA sequencing identified a p.M90I missense mutation in the NCI-H2110 cell line. Knockdown of RIT1 in NCI-H2110 cells revealed the role of RIT1 in regulation of PI3K and MEK signaling. Consistently, combination PI3K/mTOR/MEK inhibition could inhibit cellular transformation induced by ectopic expression of mutated RIT1, and PI3K/mTOR inhibition suppressed in vivo tumor growth of NCI-H2110 cells.
Recently, RIT1 mutations were described in myeloid malignancies and Noonan syndrome. Our data, together with these reported observations, indicate that RIT1 is a RAS-pathway oncogene in lung adenocarcinoma. In addition, PI3K/mTOR inhibition with or without MEK inhibition should be explored as a therapeutic strategy for RIT1-mutated lung or other RIT1-mutated cancers. This work expands the number of U.S. lung adenocarcinoma tumors with identified driver events from 62% to 75% and nominates these additional alterations as candidate therapeutic targets.
This abstract is also presented as Poster B26.
Citation Format: Alice H. Berger, Angela N. Brooks, Marcin Imielinski, Andrew Cherniack, Fujiko Duke, Nathan Kaplan, Jeremiah Wala, Matthew Meyerson. NF1, MET, and RIT1 mutations are RAS-pathway driver events in lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr PR08. doi: 10.1158/1557-3125.RASONC14-PR08