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Matthew K Stein
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.07 - JAK Pseudokinase Domain Variants Highlight nRTK nsSNPs Identified with Next-Generation Sequencing in NSCLC Patients (ID 10429)
16:25 - 16:30 | Presenting Author(s): Matthew K Stein
- Abstract
- Presentation
Background:
Non-receptor tyrosine kinase (nRTK) pathways are aberrantly activated in cancer, and mutations in nRTKs have potential therapeutic and prognostic importance. Tumor profiling with next-generation sequencing (NGS)enables a gene’s entire coding sequence to be evaluated, facilitating the identification of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in nRTKs.
Method:
We searched nsSNPs in 14 nRTKs in the tumors of advanced NSCLC patients (pts) at our institution that received NGS with Caris from 2013-2015. All mutations test-defined as pathogenic (PATH) or nsSNPs labelled variants of undetermined significance (VUS) were included. To classify VUS, nsSNPs underwent PolyPhen-2’s in silico analysis to predict pathogenicity. Any VUS predicted-damaging with PolyPhen-2 we denote pnsSNP. nsSNPs were then classified as occurring within or outside of the tyrosine kinase domain (TKD); JAK1-3 pseudokinase domain (PSKD) lesions were also described.
Result:
157 NSCLC pts were identified with median age 65 (range 26-85); 51% were male; 65% Caucasian, 35% African-American. 98 nRTK variants were found (93 nsSNPs and 5 PATHs). 5/5 PATHS were PIK3CA. 31/93 (33%) nsSNPs were pnsSNPs and spread among 30 pts. pnsSNPs were found in 12/14 nRTKs with median 2 (range 0-6). The most frequent were JAK3 (6/20 nsSNPs were pnsSNPs), BTK (5/8), ABL1 (3/12), JAK2 (3/11), CDK12 (3/9) and JAK1 (3/3). 66% were extra-TKD (28% were pnsSNP), 23% TKD-restricted (44%) and 11% PSKD of JAK1-3 (100%). There were 6 N-lobe PSKD, 3 C-lobe PSKD and 1 C-lobe TKD JAK1-3 pnsSNPs (Table 1) at PSKD-TKD contact sites known to harbor the majority of activating JAK mutations. 6/12 JAK pnsSNPs were in pts whose tumors were EGFR-/KRAS-/ALK-/ROS-/PDL1-. Table 1: JAK1-3 pnsSNPs in NSCLC patients.JAK VUS; allele frequency Location Accession Number; Minor allele frequency (ExAC) Histology Age, race, gender Genomics (EGFR, KRAS, ALK or ROS1-rearranged, PDL1 (%)) JAK1 D660N; 66% PSKD; N-lobe rs368904859; T=2.0e-5 Adeno-carcinoma 66, C, M Negative P674S; 9% PSKD; N-lobe None Squamous 76, C, M PDL1+ (5%) D739N; 47% PSKD; N-lobe rs759709239; T=3.3e-5 Large cell 43, C, M KRAS+ JAK2 E621D; 30% PSKD; N-lobe None Unspecified 65, AA, M Negative D686H; 13% PSKD; N-lobe None Adeno-carcinoma 55, C, M Negative C1105F; 41% TKD; C-lobe None Adeno-carcinoma 73, C, F KRAS+, ROS1-rearranged JAK3 V55E; 13% FERM None Adeno-carcinoma 74, C, F Negative Y105H; 21% FERM None Squamous 68, C, F PDL1+ (20%) R537Q; 47% PSKD; N-lobe rs587778413; T=4.1e-5 Adeno-carcinoma 60, C, F PDL1+ (65%) L702P; 53% PSKD; C-lobe rs772117537; G=1.7e-5 Squamous 80, C, M Negative P745L; 50% PSKD; C-lobe rs776106625; A=8.3e-6 Adeno-carcinoma 68, C, M EGFR+ (E746_A750del) L788I; 7% PSKD; C-lobe None Squamous 68, AA, M Negative
Conclusion:
>19% NSCLC pts held a pnsSNP with 77% occurring outside of the TKD-proper. The majority of JAK1-3 pnsSNPs localized to the PSKD; their frequency and functional impact should be examined on a larger scale.
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