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Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia

Zachary R. Hunter, Lian Xu, Nickolas Tsakmaklis, Maria G. Demos, Amanda Kofides, Cristina Jimenez, Gloria G. Chan, Jiaji Chen, Xia Liu, Manit Munshi, Joshua Gustine, Kirsten Meid, Christopher J. Patterson, Guang Yang, Toni Dubeau, Mehmet K. Samur, Jorge J. Castillo, Kenneth C. Anderson, Nikhil C. Munshi and Steven P. Treon

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Mutations identified in MYD88WTWM by whole exome sequencing. (A) The median number of somatic mutations for patients with paired tumor/germline samples was 33 and the number of mutations per patient for these individuals are shown. (B) Somatic mutations were associated with NF-κB signaling, epigenetic regulation, and DNA damage response. Each row represents a unique patient. Patient identifiers in bold type indicate that the patient is deceased. *Patients with disease that later transformed. (C) Location of conserved motifs in the protein coding domains of top affected genes are shown. ★Location of a somatic mutation.

  • Figure 2.

    Comparison of findings for MYD88WTand MYD88MUTWM. Comparison of somatic mutation frequencies between MYD88WT and MYD88MUT WM patients. (A) Data for mutation frequencies for 53 MYD88MUT WM patients were acquired from our previous whole genome sequencing results, using high-quality somatic variants supported by at least 3 reads.10,11 (B) Kaplan-Meier curves for overall survival from time of diagnosis for WM patients with MYD88MUT, and MYD88WT with and without DDR mutations (log-rank P < .0001).

  • Figure 3.

    Findings from next-generation gene expression studies in MYD88WTWM. (A) The top 100 most statistically significant genes between samples from 18 MYD88WT and 75 MYD88MUT patients are shown, demonstrating a uniform gene signature associated with the MYD88WT population. (B) Principal component analysis of the top 500 high variance genes revealed a clustering of MYD88WT and MYD88MUT WM samples, regardless of CXCR4 mutation status that was distinct from healthy donor peripheral blood B, memory B, and plasma cells. (C) These findings were also recapitulated in the supervised clustering of the top 100 most statistically significant differentially expressed genes between healthy donor memory B cells and MYD88WT WM samples, in which gene expression levels were very similar between all WM samples regardless of MYD88 and CXCR4 mutation status.

  • Figure 4.

    Genomic variants identified in MYD88 wild-type WM that affect NF-κB signaling. Red triangle denotes variants identified by whole exome sequencing in MYD88 wild-type WM patients.

Tables

  • Table 1.

    Patient clinical characteristics

    MedianRange or %
    Age, y5942-81
    Sex10 males/8 femalesNA
    BM, %12.52.5-80
    sIgM, mg/dL2625610-5620
    Hb, g/dL11.08.1-14.4
    Adenopathy9 (50%)NA
    Splenomegaly7 (38.8%)NA
    Prior therapies10-4
    Untreated, n844.4%
    Previously treated, n1055.5%
     Rituximab monotherapy220.0%
     Alkylators770.0%
     Nucleoside analogs550.0%
     Proteasome inhibitors550.0%
    • Hb, hemoglobin; NA, not available; sIgM, serum IgM.

  • Table 2.

    Observed somatic mutations in MYD88WT WM

    GeneConsequenceChrPositionVariantProteinCOSMICCADD
    BCL10Nonsense185733609T/Ap.135R>*COSM22063838
    BCL10Frameshift185733357-8−/AGAGTTTGCACAAGp.-/218-219LVQTXNA
    CXCR4Deletion2136872441-82TCTGTTTCCACTGAGTC TGAGTCTTCAAGTTTT CACTCCAGCTaa/taap.SVSTESESSSFH SS*339-353*NA
    CXCR4Frameshift2136872566-7−/Tp.T315NXNA
    CXCR4Missense2136873098G/Tp.R134S26.9
    NFKBIZMissense3101574709A/Cp.K45T26.3
    TBL1XR1Missense3176743302A/Gp.510L>S26.1
    TBL1XR1Missense3176744171G/Ap.S503LCOSM500034334
    TBL1XR1Splice acceptor3176750925C/GNA25.8
    TBL1XR1Deletion3176756175-7AAG/−p.SC324-325CCOSM3205534NA
    TBL1XR1Nonsense3176767829G/Ap.Q220*39
    TBL1XR1Missense3176768267C/Gp.G187GR33
    TBL1XR1Frameshift3176769342T/−p.N126NXCOSM142070634
    PTPN13Missense487556423T/Ap.L5Q33
    PTPN13Missense487656789G/Tp.A732SCOSM501985927.6
    PTPN13Missense487683919A/Cp.N1198T3.649
    PTPN13Missense487696460C/Ap.P1882QCOSM48165025.4
    NFKB1Missense4103459060G/Ap.G69R31
    KMT2CNonsense7151891205C/Ap.G1517*COSM330422441
    NOTCH1Nonsense9139390945G/Ap.Q2416*COSM477510841
    NFKB2Deletion10104160996-1855NANANA
    NFKB2Deletion10104160849-1688NANANA
    ATMNonsense11108175504C/Tp.Q1867*37
    ATMMissense11108204685T/Cp.M2667T26.3
    KMT2DFrameshift1249433373-4−/G CCG CCCCCCTp.-2691-NA
    2692AAPX
    KMT2DMissense1249445543T/Gp.E641D5.499
    KMT2DMissense1249446710G/Tp.P367Q11.92
    KMT2DFrameshift1249448408G/−p.G101X'NA
    TP53Missense177577108C/Ap.C277FCOSM56233834
    TP53Missense177577114C/Ap.C275FCOSM9993234
    MALT1Nonsense1856414859C/Tp.Q743*36
    MALT1Nonsense1856414882C/Ap.Y750*36
    NFKBIBFrameshift1939398226-7CT/−p.P299XCOSM5081722NA
    UFD1LMissense2219443248C/Ap.G145V23.6
    KDM6AMissenseX44911044T/Ap.L249I25.4
    KDM6AFrameshiftX44942757G/−p.V1113XCOSM5031082NA
    KDM6AFrameshiftX44922936-7−/GGAAGTGGAAGTp-/.599-NA
    AAT GGAAAC GTGCC600GSGSNGNVX
    • CADD, combined annotation dependent depletion; chr, chromosome; COSMIC, Catalogue of Somatic Mutations in Cancer.