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.
| Original language | English |
|---|---|
| Journal | Journal of Thoracic Oncology |
| Volume | 14 |
| Issue number | 4 |
| Pages (from-to) | 606-616 |
| Number of pages | 11 |
| ISSN | 1556-0864 |
| DOIs | |
| Publication status | Published - 04.2019 |
Funding
Disclosure: Dr. Scheffler has received honoraria from Novartis, BMS, and Boehringer Ingelheim; has had advisory roles for Novartis and Boehringer Ingelheim; and has received travel support/accommodations from Novartis, Boehringer Ingelheim, and BMS. Dr. Merkelbach-Bruse has received honoraria from AstraZeneca and had advisory roles for AstraZeneca and Roche. Dr. Scheel has had advisory roles for MSD, BMS, Roche, AstraZeneca, and Pfizer. Dr. Michels has received honoraria from Novartis, Pfizer, AstraZeneca, and Boehringer Ingelheim; has had advisory roles for Boehringer Ingelheim and Pfizer; has received research funding from Pfizer, Novartis, and BMS; and has received travel support/accommodations from Novartis. Dr. Fassunke has received honoraria from and has had an advisory role for AstraZeneca. Dr. Pasternack has received honoraria and travel support/accommodations from Roche and had advisory roles for AstraZeneca and Novartis. Dr. Fischer has received honoraria and travel support from BMS and Boehringer Ingelheim and has had an advisory role for BMS. Dr. Nogova has received honoraria from Pfizer and Celgene; has had advisory roles for Roche, Novartis, and Boehringer Ingelheim; and has received travel accommodations from Novartis, Pfizer, and Celgene. Dr. Kambartel has had advisory roles for Boehringer Ingelheim, BMS, MSD, Roche, and Pfizer and has received research funding from BMS and MSD. Dr. Thomas is founder of NEO New Oncology. Dr. Sos has received research funding from Novartis. Dr. Wolf has received honoraria from AstraZeneca, BMS, Clovis Oncology, Lilly, MSD, Novartis, Pfizer, and Roche; has had advisory roles for AstraZeneca, BMS, Clovis Oncology, Lilly, MSD, Novartis, Pfizer, Roche, and AMGEN; has received research funding from BMS, Bayer, MSD, Novartis, Pfizer, and Boehringer Ingelheim; and has received travel support by BMS, MSD, Novartis, Pfizer, and Roche. The remaining authors declare no conflict of interest. Disclosure: Dr. Scheffler has received honoraria from Novartis, BMS, and Boehringer Ingelheim; has had advisory roles for Novartis and Boehringer Ingelheim; and has received travel support/accommodations from Novartis, Boehringer Ingelheim, and BMS. Dr. Merkelbach-Bruse has received honoraria from AstraZeneca and had advisory roles for AstraZeneca and Roche. Dr. Scheel has had advisory roles for MSD, BMS, Roche, AstraZeneca, and Pfizer. Dr. Michels has received honoraria from Novartis, Pfizer, AstraZeneca, and Boehringer Ingelheim; has had advisory roles for Boehringer Ingelheim and Pfizer; has received research funding from Pfizer, Novartis, and BMS; and has received travel support/accommodations from Novartis. Dr. Fassunke has received honoraria from and has had an advisory role for AstraZeneca. Dr. Pasternack has received honoraria and travel support/accommodations from Roche and had advisory roles for AstraZeneca and Novartis. Dr. Fischer has received honoraria and travel support from BMS and Boehringer Ingelheim and has had an advisory role for BMS. Dr. Nogova has received honoraria from Pfizer and Celgene; has had advisory roles for Roche, Novartis, and Boehringer Ingelheim; and has received travel accommodations from Novartis, Pfizer, and Celgene. Dr. Kambartel has had advisory roles for Boehringer Ingelheim, BMS, MSD, Roche, and Pfizer and has received research funding from BMS and MSD. Dr. Thomas is founder of NEO New Oncology. Dr. Sos has received research funding from Novartis. Dr. Wolf has received honoraria from AstraZeneca, BMS, Clovis Oncology, Lilly, MSD, Novartis, Pfizer, and Roche; has had advisory roles for AstraZeneca, BMS, Clovis Oncology, Lilly, MSD, Novartis, Pfizer, Roche, and AMGEN; has received research funding from BMS, Bayer, MSD, Novartis, Pfizer, and Boehringer Ingelheim; and has received travel support by BMS, MSD, Novartis, Pfizer, and Roche. The remaining authors declare no conflict of interest.
