1. Genomic profiling in a homogeneous molecular subtype of non-small cell lung cancer: An effort to explore new drug targets
- Author
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B S Ajai Kumar, Diganta Hazarika, Vidya H Veldore, H P Shashidhara, Ramadas Naik, Raghavendra M Rao, N Krishnamoorthy, Shivanand Patil, Shilpa Prabhudesai, R Tejaswi, and C T Satheesh
- Subjects
Male ,Oncogene Proteins, Fusion ,Class I Phosphatidylinositol 3-Kinases ,medicine.drug_class ,medicine.medical_treatment ,Biology ,medicine.disease_cause ,Bioinformatics ,Polymorphism, Single Nucleotide ,Tyrosine-kinase inhibitor ,Targeted therapy ,Phosphatidylinositol 3-Kinases ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Molecular Targeted Therapy ,Epidermal growth factor receptor ,Receptor, Fibroblast Growth Factor, Type 2 ,Lung cancer ,Protein Kinase Inhibitors ,Genome, Human ,Fibroblast growth factor receptor 2 ,Proto-Oncogene Proteins c-ret ,High-Throughput Nucleotide Sequencing ,Kinase insert domain receptor ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,ErbB Receptors ,Oncology ,Mutation ,Cancer research ,biology.protein ,Female ,KRAS - Abstract
Background: Patients' who are positive for kinase domain activating mutations in epidermal growth factor receptor (EGFR) gene, constitute 30–40% of non-small cell lung cancer (NSCLC), and are suitable candidates for Tyrosine Kinase Inhibitor based targeted/personalized therapy. In EGFR non-mutated subset, 8–10% that show molecular abnormalities such as EML4-ALK, ROS1-ALK, KIP4-ALK, may also derive the benefit of targeted therapy. However, 40% of NSCLC belong to a grey zone of tumours that are negative for the clinically approved biomarkers for personalized therapy. This pilot study aims to identify and classify molecular subtypes of this group to address the un-met need for new drug targets in this category. Here we screened for known/novel oncogenic driver mutations using a 46 gene Ampliseq Panel V1.0 that includes Ser/Thr/Tyr kinases, transcription factors and tumor suppressors. Methods: NSCLC with tumor burden of at least 40% on histopathology were screened for 29 somatic mutations in the EGFR kinase domain by real-time polymerase chain reaction methods. 20 cases which were EGFR non-mutated for TK domain mutations were included in this study. DNA Quality was verified from each of the 20 cases by fluorimeter, pooled and subjected to targeted re-sequencing in the Ion Torrent platform. Torrent Suite software was used for next generation sequencing raw data processing and variant calling. Results: The clinical relevance and pathological role of all the mutations/variants that include SNPs and Indels was assessed using polyphen-2/SIFT/PROVEAN/mutation assessor structure function prediction programs. There were 10 pathogenic mutations in six different oncogenes for which annotation was available in the COSMIC database; C420R mutation in PIK3CA, Q472H mutation in vascular endothelial growth factor receptor 2 (VEGFR2) (KDR), C630W and C634R in RET, K367M mutation in fibroblast growth factor receptor 2 (FGFR2), G12C in KRAS and 4 pathogenic mutations in TP53 in the DNA binding domain (E285K, R213L, R175H, V173G). Conclusion: Results suggest, a potential role for PIK3CA, VEGFR2, RET and FGFR2 as therapeutic targets in EGFR non-mutated NSCLC that requires further clinical validation.
- Published
- 2015
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