K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways.

K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways.

J Thorac Oncol. 2018 Dec 31;:

Authors: 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 YD, Abdulla DSY, Riedel R, Kambartel KO, 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

Abstract
BACKGROUND: While KRAS mutations in non-small cell lung cancer (NSCLC) have been considered as mutually exclusive driver mutations for a long time, there is growing evidence now that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related comutations and their correlation with different KRAS mutation subtypes.
METHODS: Diagnostic samples of 4507 NSCLC patients were analyzed by next-generation sequencing (NGS) using a panel of 14 genes and, in a subset of patients, fluorescence in-situ hybridization (FISH). NGS with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing (WES) was performed in two patients.
RESULTS: We identified 1078 patients with KRAS mutations, whereof 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Beside mutations inTP53 (39.4%), STK11 (19.8%), KEAP1 (12.9%), ATM (11.9%), as well as MET amplifications (15.4%) and ERBB2 amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). WES of two patients with co-occurring 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.

PMID: 30605727 [PubMed - as supplied by publisher]

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