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 alterations and TP53 mutations. Therapeutic strategies targeting KRAS activation, including inhibitors of MAP kinase signaling, may warrant investigation in NF1 mutant tumors. Tumor suppressor inactivation patterns may help further define novel treatment strategies.

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

“…Nf1 loss accelerates Kras;p53-mutant LUAD tumorigenesis 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, 2016), 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 1A).…”

Institutional implementation of clinical tumor profiling on an unselected cancer population

“…Indeed, this initiative has enabled a large number of other more focused studies of common and uncommon tumor types and, in particular, has permitted prospective identification of relatively uncommon genomic variants to facilitate clinical trial enrollment and biomarker studies (46)(47)(48)(49)(50)(51)(52)(53)(54). Migrating to a clinical test, identifying when in the course of a patient's disease genomic profiling should be used, and triaging patients in real-time for clinical trial enrollment should contribute to determining clinical utility on a broader scale.…”

mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors

“…MPNSTs that arise in individuals with NF1 are inherently more homogeneous as compared to lung cancer, in that they are initiated by NF1 mutations and progress due to a specific set of additional genetic alterations (47–49). In contrast, lung cancers are much more genetically and biologically heterogeneous (50,51). While 4/5 of the RAS pathway-driven lung cancers evaluated in this study were sensitive to these agents, further study is needed to establish whether NF1 and KRAS mutations are predictive biomarkers, and/or if other predictive biomarkers exist.…”