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M.G. Martin



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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  |  Author(s): M.G. Martin

      • Abstract
      • Presentation
      • Slides

      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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