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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
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      MA 06.07 - JAK Pseudokinase Domain Variants Highlight nRTK nsSNPs Identified with Next-Generation Sequencing in NSCLC Patients (ID 10429)

      15:45 - 17:30  |  Presenting Author(s): Matthew K Stein

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      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

      >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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