Clinical and molecular characteristics of NF1 mutant lung cancer.

Abstract

Background-NF1 is a tumor suppressor that negatively regulates Ras signaling. NF1 mutations occur in lung cancer, but their clinical significance is unknown. We evaluated clinical and molecular characteristics of NF1 mutant lung cancers with comparison to tumors with KRAS mutations. Methods-Between July 2013 and October 2014, 591 NSCLC tumors underwent targeted next generation sequencing in a 275 gene panel that evaluates gene mutations and genomic rearrangements. NF1 and KRAS cohorts were identified, with subsequent clinical and genomic analysis. Results-Among 591 pts, 60 had NF1 mutations (10%) and 141 (24%) had KRAS mutations. 15 NF1 mutations (25%) occurred with other oncogenic mutations (BRAF (2); ERBB2 (2); KRAS (9); HRAS (1); NRAS (1)). There were 72 unique NF1 variants. NF1 tumor pathology was diverse, including both adenocarcinoma (36, 60%) and squamous cell carcinoma (10, 17%). In contrast, KRAS mutations occurred predominantly in adenocarcinoma (136, 96%). Both mutations were common in former/current smokers. Among NF1 tumors without concurrent oncogenic alterations, TP53 mutations/2-copy deletions occurred more often (33, 65%) than with KRAS mutation (46, 35%) (p<.001). No difference between cohorts was seen with other tumor suppressors. Conclusions-NF1 mutations define a unique population of NSCLC. NF1 and KRAS mutations present in similar patient populations, but NF1 mutations occur more often with other oncogenic

Frequency and clinical significance of NF1 mutation in lung adenocarcinomas from East Asian patients

“…In a recent study of 591 NSCLC, the prognosis of NF1 mutation was investigated. The overall survival of patients whose tumors harbored an NF1 mutation was similar with patients whose tumors harbored a KRAS mutation . Consistent with our study, NF1 ‐mutant patients have similar DFS and OS comparing with KRAS ‐mutant patients with surgically curative intent.…”

“…The NF1‐ mutant cohort is relatively driver mutation exclusive, with 75% of mutations occurring independently from known oncogenic alterations, although there is some overlap in tumors harboring both mutations . In our study, however, 71% (22/31) of NF1 mutations overlapped with known driver mutations, mostly with EGFR mutation (14/31, 45.2%).…”

“…In lung cancer, NF1 mutation occurred in 10% of nonsmall cell lung cancers in Western populations, which were only found in 7% of sporadic lung adenocarcinomas . Imielinski and colleagues reported that somatic NF1 mutations occurred in 10.9% (20/183) of lung adenocarcinomas, of which half were truncating mutations, resulting in a complete loss of function .…”

“…NF1 mutation is generally supposed to be a novel “driver mutation” candidate because of its nearly mutual exclusion with other classic drivers. Subsequent study revealed that NF1 ‐mutant lung cancers shared common clinical and molecular characteristics with KRAS ‐mutant lung cancers due to the similar RAS activation signaling after somatic mutation . Although KRAS protein could not be directly targeted by small molecular agents, recent efforts have demonstrated that inhibition of MAP kinase signaling may be effective in KRAS ‐mutant NSCLC .…”

Nf1 loss promotes Kras ‐driven lung adenocarcinoma and results in Psat1‐mediated glutamate dependence

“…As TP53 mutations show prognostic significance in KRAS‐ mutant LUAD cases and NF1 ‐mutant LUAD tumors show significantly higher rates of TP53 mutation relative to KRAS‐ mutant LUAD tumors (Redig et al , ), we investigated the cooperative effect of silencing Nf1 and p53 expression on the oncogenicity of constitutively active Kras mutants. Using CRISPR‐Cas9 technology, the Kras LSL‐G12D/+ ; p53 fl/fl (KP) murine model of Kras ‐driven LUAD was engineered to silence Nf1 and p53 expression (Fig A).…”