Ernest Nadal1, Guoan Chen, John R Prensner, Hiroe Shiratsuchi, Christine Sam, Lili Zhao, Gregory P Kalemkerian, Dean Brenner, Jules Lin, Rishindra M Reddy, Andrew C Chang, Gabriel Capellà, Felipe Cardenal, David G Beer, Nithya Ramnath. 1. *Thoracic Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan; †Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan; ‡Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; §Department of Biostatistics, University of Michigan, Ann Arbor, Michigan; ‖Veterans Administration Medical Center, Ann Arbor, Michigan; ¶Translational Research Laboratory, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain; and #Department of Medical Oncology, Thoracic Oncology Multidisciplinary Unit, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
Abstract
INTRODUCTION: The aim of this study was to examine the effects of KRAS mutant subtypes on the outcome of patients with resected lung adenocarcinoma (AC). METHODS: Using clinical and sequencing data, we identified 179 patients with resected lung AC for whom KRAS mutational status was determined. A multivariate Cox model was used to identify factors associated with disease-free survival (DFS) and overall survival (OS). Publicly available mutation and gene-expression data from lung cancer cell lines and lung AC were used to assess whether distinct KRAS mutant variants have a different profile. RESULTS: Patients with KRAS mutation had a significantly shorter DFS compared with those with KRAS wild-type (p = 0.009). Patients with KRAS-G12C mutant tumors had significantly shorter DFS compared with other KRAS mutants and KRAS wild-type tumors (p < 0.001). In the multivariate Cox model, KRAS-G12C remained as an independent prognostic marker for DFS (Hazard ratio = 2.46, 95% confidence interval 1.51-4.00, p < 0.001) and for OS (Hazard ratio = 2.35, 95% confidence interval 1.35-4.10, p = 0.003). No genes were statistically significant when comparing the mutational or transcriptional profile of lung cancer cell lines and lung AC harboring KRAS-G12C with other KRAS mutant subtypes. Gene set enrichment analysis revealed that KRAS-G12C mutants overexpressed epithelial to mesenchymal transition genes and expressed lower levels of genes predicting KRAS dependency. CONCLUSIONS: KRAS-G12C mutation is associated with worse DFS and OS in resected lung AC. Gene-expression profiles in lung cancer cell lines and surgically resected lung AC revealed that KRAS-G12C mutants had an epithelial to mesenchymal transition and a KRAS-independent phenotype.
INTRODUCTION: The aim of this study was to examine the effects of KRAS mutant subtypes on the outcome of patients with resected lung adenocarcinoma (AC). METHODS: Using clinical and sequencing data, we identified 179 patients with resected lung AC for whom KRAS mutational status was determined. A multivariate Cox model was used to identify factors associated with disease-free survival (DFS) and overall survival (OS). Publicly available mutation and gene-expression data from lung cancer cell lines and lung AC were used to assess whether distinct KRAS mutant variants have a different profile. RESULTS: Patients with KRAS mutation had a significantly shorter DFS compared with those with KRAS wild-type (p = 0.009). Patients with KRAS-G12C mutant tumors had significantly shorter DFS compared with other KRAS mutants and KRAS wild-type tumors (p < 0.001). In the multivariate Cox model, KRAS-G12C remained as an independent prognostic marker for DFS (Hazard ratio = 2.46, 95% confidence interval 1.51-4.00, p < 0.001) and for OS (Hazard ratio = 2.35, 95% confidence interval 1.35-4.10, p = 0.003). No genes were statistically significant when comparing the mutational or transcriptional profile of lung cancer cell lines and lung AC harboring KRAS-G12C with other KRAS mutant subtypes. Gene set enrichment analysis revealed that KRAS-G12C mutants overexpressed epithelial to mesenchymal transition genes and expressed lower levels of genes predicting KRAS dependency. CONCLUSIONS: KRAS-G12C mutation is associated with worse DFS and OS in resected lung AC. Gene-expression profiles in lung cancer cell lines and surgically resected lung AC revealed that KRAS-G12C mutants had an epithelial to mesenchymal transition and a KRAS-independent phenotype.
Authors: Peter R Bucciarelli; Kay See Tan; Neel P Chudgar; Whitney Brandt; Joseph Montecalvo; Takashi Eguchi; Yuan Liu; Rania Aly; William D Travis; Prasad S Adusumilli; David R Jones Journal: J Thorac Oncol Date: 2017-10-31 Impact factor: 15.609
Authors: Vincent L Cannataro; Stephen G Gaffney; Carly Stender; Zi-Ming Zhao; Mark Philips; Andrew E Greenstein; Jeffrey P Townsend Journal: Oncogene Date: 2018-02-16 Impact factor: 9.867