Localization of non-receptor tyrosine kinase (nRTK) variants identified in solid tumor patients with Next-Generation Sequencing (NGS)
Srishti Sareen, Matthew K Stein, Lindsay K Morris, Saradasri Karri, Kruti Patel, David Shibata, Ari M Vanderwalde, Lee S Schwartzberg, Mike G Martin
Non-synonymous single nucleotide polymorphisms (nsSNPs) in non receptor tyrosine kinases (nRTKs) may serve as oncologic targets and predictive biomarkers, with significant lesions described in various nRTK regions including the tyrosine kinase domain (TKD).
Next Generation Sequencing (NGS) allows the entire coding sequence to be evaluated.
This facilitates the identification of novel lesions.
We searched all nsSNPs in 14 nRTKs in the tumors of patients (pts) at our institution that received NGS with Caris Life Sciences1 from 2013-2015 with a diagnosis of advanced breast, colon or lung cancer.
Substitutions were classified as either within or extra-TKD; in the case of JAK1-3, pseudokinase domain lesions were also identified.
In order to predict the pathogenicity of nsSNPs, in silico analysis with PolyPhen-2 (Harvard)2,3 was completed.
13% of breast, colon, and lung tumors harbored an nRTK nsSNP that was predicteddamaging by in silico analysis.
68% of these mutations occurred outside of the TKD, with an additional 9% in JAK1-3 pseudokinase domain.
NGS can identify nsSNPs in various nRTK regulatory domains that warrant further characterization.
Further work is needed to determine how these pnsSNPs affect function and if they are clinically actionable.