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K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways
- Source :
- Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 14(4)
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
Pulmonary and Respiratory Medicine
Adult
Male
Lung Neoplasms
STK11
medicine.disease_cause
Receptor tyrosine kinase
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
0302 clinical medicine
Carcinoma, Non-Small-Cell Lung
Medicine
Humans
neoplasms
Gene
Aged
Aged, 80 and over
Mutation
biology
medicine.diagnostic_test
business.industry
Kinase
Genetic heterogeneity
Middle Aged
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
biology.protein
Cancer research
Female
KRAS
business
Fluorescence in situ hybridization
Subjects
Details
- ISSN :
- 15561380
- Volume :
- 14
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
- Accession number :
- edsair.doi.dedup.....126be135328e3f2bcf25497758c58a3b