K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways.
INTRODUCTION:Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes. METHODS:Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients. RESULTS:We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. CONCLUSION:KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.
Scheffler, M; Ihle, MA; Hein, R; Merkelbach-Bruse, S; Scheel, AH; Siemanowski, J; Brägelmann, J; Kron, A; Abedpour, N; Ueckeroth, F; Schüller, M; Koleczko, S; Michels, S; Fassunke, J; Pasternack, H; Heydt, C; Serke, M; Fischer, R; Schulte, W; Gerigk, U; Nogova, L; Ko, Y-D; Abdulla, DSY; Riedel, R; Kambartel, K-O; Lorenz, J; Sauerland, I; Randerath, W; Kaminsky, B; Hagmeyer, L; Grohé, C; Eisert, A; Frank, R; Gogl, L; Schaepers, C; Holzem, A; Hellmich, M; Thomas, RK; Peifer, M; Sos, ML; Büttner, R; Wolf, J
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