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Table 2 Sub-classification of potentially targetable somatic mutations for treatment planning

From: Implementation of next generation sequencing into pediatric hematology-oncology practice: moving beyond actionable alterations

PIP ID Diagnosis Target alteration Mutation (change) Potential target therapy
Tier 1 (Data demonstrating benefit- same tumor type, same gene)
 14-85546 CML BCR-ABL1 Fusion TKI
 13-45348a AML IDH1 c.394C > T (p.R132C) IDH Inhibitor
 14-24794a AML c-KIT; TET2; FLT3 c.2446G > C (p.D816H); c.3663delT (p.C1221Wfs); c.2505 T > G (p.D835E) TKI; Hypomethylating agent; TKI
 14-53198 AML TET2 c.1156G > T (p.V386L) Hypomethylating agent
 13-77086 AML c-KIT c.1965 T > G (p.Asn655Lys) TKIb
Tier 2 (Data demonstrating benefit- different tumor type, same gene)
 15-18928 Hepatic rhabdoid tumor SMARCA4 c.3574C > T (p.R1192C) EZH2 Inhibitor
 14-13487 Osteosarcoma TSC1 c.2503-1G > C (p.?) mTOR Inhibitor
 14-47205 Nephroblastomatosis PIK3CA c.1035 T > A (p.N345K) PI3K/AKT/mTOR Inhibitor
 15-40141 Pleomorphic xanthoastrocytoma TMEM106B-BRAF Fusion MEK Inhibitor
Tier 3 (Published, presented, in press pre-clinical data demonstrating benefit- same tumor type, same gene)
 15-64793 ALL FOXP1-ABL1 Fusion TKIb
 15-26188 ALL NUP214-ABL1 Fusion TKIb
 15-79700 ALL NRAS c.183A > T (p.Q61H) MEK Inhibitor
 14-20062 ALL KRAS c.183A > T (p.Q61H) MEK Inhibitor
 14-24794a AML NRAS c.183A > C (p.Q61H) MEK Inhibitor
 15-29224 AML JAK3 c.1718C > T (p.A573V) JAK Inhibitor
 13-45348a AML NRAS c.38G > C (p.G13A) MEK Inhibitor
 13-95124 AML NRAS; MLL-AFF1 (KMT2A-AFF1) c.182A > G (p.Q61R); Fusion MEK Inhibitor; DOT1L Inhibitor
 14-45760 AML NRAS c.38G > A (p.G13D) MEK Inhibitor
 13-50662 AML PTPN11 c.1508G > T (p.G503V) MEK Inhibitor
 14-15491 AML NUP98-NSD1 Fusion DOT1L Inhibitor
 14-27243 Neuroblastoma NRAS c.181C > A (p.Q61K) MEK Inhibitor
 14-70449 Rhabdomyosarcoma NRAS c.181C > A (p.Q61K) MEK Inhibitor
 14-42817 Neuroblastoma KRAS c.34G > T (p.G12C) MEK Inhibitor
 15-11925a Osteosarcoma MYC Overexpression BET Inhibitor
 16-74654 Rhabdomyosarcoma FGFR4 c.1582G > T (p.G528C); c.1648G > C (p.V550L) FGFR4 Inhibitor
 15-23518 Rhabdomyosarcoma FGFR4 c.1648G > C (p.V550L); c.1949G > T (p.R650L); Overexpression FGFR4 Inhibitor
 14-37237 Glioblastoma multiforme Gain 12q.14.1 involving CDK2 Copy number CDK4/6 Inhibitor
 15-44470 Medulloblastoma PTCH1, SUFU, ZIC3 Overexpression SMO Inhibitor
 15-10838 Glioma H3F3A; FGFR1 c.83A > T (p.K28M); c.1731C > A (p.N577K) HDAC Inhibitor
 15-27992 Hepatic rhabdoid tumor Homozygous deletion of chr 22q11.23 with homozygous deletion of SMARCB1; Loss of expression of SMARCB1 Copy number; Loss of expression with biallelic deletion EZH2 Inhibitor
Tier 4 (Published, presented, in press pre-clinical data demonstrating benefit- different tumor type, same gene)
 15-36388 AML MLL3 (KMT2C) c.2110G > T (p.E704X) BET Inhibitor
 13-72282 T-ALL KRAS; JAK1; STAT5B c.40G > A (p.V14I); c.3076A > G (p.K1026E); c.2110A > C (p.I704L) MEK Inhibitor; JAK Inhibitor; BCL2/BCLX-L Inhibitor
 15-66870 Adrenocortical carcinoma ALK c.3436C > A (p.Q1146K) ALK Inhibitorb
Tier 5 (Anything else the molecular tumor board thought was sufficient to qualify for treatment planning)
 15-16072 ALL SMARCC2-PDGFRB Fusion TKI
 14-75899 Neuroblastoma CDK4, MDM2 Overexpression NEPENTHE trial [NCT02780128]
 15-11925a Osteosarcoma MCL1, CCNE1 Overexpression CDK4/6 Inhibitor
 15-35162 Osteosarcoma CUL4A Overexpression NAE Inhibitor
 14-71727 Osteosarcoma RAD51C c.24 T > G (p.F8L) PARP Inhibitor
 15-83826 Osteosarcoma PDGFRA, KDR (VEGFR2) Overexpression MTKIb
 13-21968 Congenital fibrosarcoma EML4-NTRK3 Fusion ALK Inhibitor
 14-84044 Inflammatory myofibroblastic tumor VCAN-IL23R Fusion JAK Inhibitorb
  1. aSame patient
  2. bTargeted therapy received
  3. ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, CML chronic myeloid leukemia
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