K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways

Matthias Scheffler, Michaela A. Ihle, Rebecca Hein, Sabine Merkelbach-Bruse, Andreas H. Scheel, Janna Siemanowski, Johannes Brägelmann, Anna Kron, Nima Abedpour, Frank Ueckeroth, Merle Schüller, Sophia Koleczko, Sebastian Michels, Jana Fassunke, Helen Pasternack, Carina Heydt, Monika Serke, Rieke Fischer, Wolfgang Schulte, Ulrich GerigkLucia Nogova, Yon Dschun Ko, Diana S.Y. Abdulla, Richard Riedel, Karl Otto Kambartel, Joachim Lorenz, Imke Sauerland, Winfried Randerath, Britta Kaminsky, Lars Hagmeyer, Christian Grohé, Anna Eisert, Rieke Frank, Leonie Gogl, Carsten Schaepers, Alessandra Holzem, Martin Hellmich, Roman K. Thomas, Martin Peifer, Martin L. Sos, Reinhard Büttner, Jürgen Wolf*

*Corresponding author for this work
20 Citations (Scopus)


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.

Original languageEnglish
JournalJournal of Thoracic Oncology
Issue number4
Pages (from-to)606-616
Number of pages11
Publication statusPublished - 04.2019


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