title: Clinical and Molecular Characteristics of NF1-Mutant Lung Cancer.
abstract: 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.
  
  
  
  Between July 2013 and October 2014, 591 non-small cell lung cancer (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.
  
  
  
  Among 591 patients, 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 < 0.001). No difference between cohorts was seen with other tumor suppressors.
  
  
  
  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. Clin Cancer Res; 22(13); 3148-56. ©2016 AACR.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Amanda J
authors: AJ
authors: Redig
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors: Marzia
authors: M
authors: Capelletti
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors: Suzanne E
authors: SE
authors: Dahlberg
authors: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Lynette M
authors: LM
authors: Sholl
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Stacy
authors: S
authors: Mach
authors: Information Systems, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Caitlin
authors: C
authors: Fontes
authors: Information Systems, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Yunling
authors: Y
authors: Shi
authors: Information Systems, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Poornima
authors: P
authors: Chalasani
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu.
authors: Pasi A
authors: PA
authors: Jänne
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D025542:Neurofibromin 1 / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D025542:Neurofibromin 1; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)