Scheffler, Matthias, Ihle, Michaela A., Hein, Rebecca, Merkelbach-Bruse, Sabine, Scheel, Andreas H., Siemanowski, Janna, Braegelmann, Johannes, Kron, Anna, Abedpour, Nima, Ueckeroth, Frank, Schueller, Merle, Koleczko, Sophia, Michels, Sebastian, Fassunke, Jana, Pasternack, Helen, Heydt, Carina, Serke, Monika, Fischer, Rieke, Schulte, Wolfgang, Gerigk, Ulrich, Nogova, Lucia, Ko, Yon-Dschun, Abdulla, Diana S. Y., Riedel, Richard, Kambartel, Karl-Otto, Lorenz, Joachim, Sauerland, Imke, Randerath, Winfried, Kaminsky, Britta, Hagmeyer, Lars, Grohe, Christian, Eisert, Anna, Frank, Rieke, Gogl, Leonie, Schaepers, Carsten, Holzem, Alessandra, Hellmich, Martin, Thomas, Roman K., Peifer, Martin, Sos, Martin L., Buettner, Reinhard and Wolf, Juergen (2019). K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways. J. Thorac. Oncol., 14 (4). S. 606 - 617. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1556-1380

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Abstract

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. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Scheffler, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihle, Michaela A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hein, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheel, Andreas H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siemanowski, JannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kron, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abedpour, NimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ueckeroth, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schueller, MerleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koleczko, SophiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasternack, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heydt, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serke, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, RiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerigk, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nogova, LuciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ko, Yon-DschunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdulla, Diana S. Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riedel, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kambartel, Karl-OttoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sauerland, ImkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Randerath, WinfriedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaminsky, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hagmeyer, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grohe, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eisert, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frank, RiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gogl, LeonieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaepers, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzem, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hellmich, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-152848
DOI: 10.1016/j.jtho.2018.12.013
Journal or Publication Title: J. Thorac. Oncol.
Volume: 14
Number: 4
Page Range: S. 606 - 617
Date: 2019
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1556-1380
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL LUNG-CANCER; COOCCURRING GENOMIC ALTERATIONS; KRAS MUTATIONS; PROGNOSTIC IMPACT; PREDICTIVE-VALUE; PHASE-II; CHEMOTHERAPY; ADENOCARCINOMA; AMPLIFICATION; THERAPYMultiple languages
Oncology; Respiratory SystemMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15284

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