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Impact of somatic and germline mutations on the outcome of systemic mastocytosis

Javier I. Muñoz-González, María Jara-Acevedo, Iván Alvarez-Twose, Jason D. Merker, Cristina Teodosio, Yanli Hou, Ana Henriques, Krishna M. Roskin, Laura Sanchez-Muñoz, Albert G. Tsai, Carolina Caldas, Almudena Matito, J. Ignacio Sánchez-Gallego, Andrea Mayado, Noelia Dasilva-Freire, Jason R. Gotlib, Luis Escribano, Alberto Orfao and Andrés C. García-Montero

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Kaplan-Meier estimates of PFS and OS of SM patients (n = 20) grouped according to the number and type of mutations detected. Panels describe PFS (left panels) and OS (right panels) of patients grouped according to the number of total genetic variants (A), germline genetic variants (B), multilineal somatic mutations (C), and MC restricted (somatic) mutations (D). Values are expressed in years from diagnosis to disease progression (PFS) and death (OS) or the last follow-up visit. Median PFS and/or OS indicates the time point at which half of the patients have progressed to more aggressive forms of the disease or died, respectively.

  • Figure 2.

    Kaplan-Meier estimates of PFS and OS of SM patients (n = 34) grouped according to the mutational status of SRSF2, ASXL1, RUNX1 and EZH2 genes. PFS (left panels) and OS (right panels) of SM patients grouped according to the presence vs absence of mutated S/A/R genes (A), the EZH2 mutational status within the S/A/R gene panel (B), and the presence vs absence of mutated S/A/R/E genes (C). Values are expressed in years from diagnosis to disease progression (PFS) and death (OS) or the last follow-up visit. Median PFS and/or OS indicates the time point at which half of the patients have progressed to more aggressive forms of the disease or died, respectively.

Tables

  • Table 1.

    Clinical and biological features of the 34 SM patients carrying the multilineal KIT mutation analyzed in this study

    Patient IDSexAge, yDiagnosisProgressionPFS, yFollow-up (at disease progression or last visit)AliveOS, yCause of progression
    WHO subtypeBM MC aggregates in histologysBT, ng/mLAge, yWHO subtypesBT, ng/mL
    1M46ISM+115No1763ISM105Yes17
    2M48ISM+210No1967ISM258Yes19
    3M67ISM+167No370ISM143Yes3
    4F71ISM+208Yes576SSM289Yes10sBT > 200; SPLEN
    5F39ISM+175Yes1554SSM240Yes17sBT > 200; SPLEN
    6M45ISM+267Yes246SSM310Yes9HEP-SPLEN; DBS
    7M66ISM+270Yes268ASM305No6HEP-SPLEN; NEUP
    8F11ISM+1077Yes1425ASM1970Yes30HEP-SPLEN*; DBS
    9M0ISM+332Yes3231ASM430Yes48HEP-SPLEN*; DBS
    10M32ISM+1298Yes3062ASM2036Yes39HEP*; DBS
    11M57ISM+362Yes663ASM1507No7HEP*; IDA
    12F47ISM+290Yes249ASM312No6SPLEN*; DBS; TRP
    Subtotal66% M, 34% F46.5 (0-71)270 (167-1298)9/12 (75%)10 (2-32)62.5 (25-76)307.5 (105-2036)9/12 (75%)13.5 (3-48)
    13M51ASM+238No657ASM174Yes6
    14F60ASM+260No1070ASM288Yes10
    15M72ASM+1469No476ASM1469Yes4
    16M66ASM+123Yes470SM-AHN53No4MPN
    17F37ASM+201Yes138SM-AHNNAYes3AML
    18M65ASM+150Yes368SM-AHN516No4MDS
    19M45ASM+548Yes449SM-AHN477No10AML
    20M58ASM+178Yes159SM-AHN235No2MDS
    21F76ASM+279Yes581ASM400No5SM-related death
    22F49SM-AHN+180No1050SM-AHN173Yes10
    23F41SM-AHN+184No344SM-AHN123Yes3
    24F53SM-AHN+159No356SM-AHN85Yes3
    25F51SM-AHN+112Yes1162SM-AHN147No11SM-related death
    26F56SM-AHN+1376Yes157SM-AHN1354No1SM-related death
    27M64ASM+180Yes1276SM-AHN107Yes12AML
    28M70ASM+308Yes171ASM308No1SM-related death
    29M59SM-AHN+160Yes160SM-AHN257No1SM-related death
    30M15SM-AHN+210No1328SM-AHN107Yes13
    31F66SSM+892No470SSM386Yes4
    32M41SSM+304No1859SSM226Yes18
    33F52SSM+316No557SSM282Yes5
    34F33SSM+187No1043SSM166Yes10
    Subtotal50% M 50% F54.5 (15-76)224 (112-1469)11/22 (50%)4 (1-18)59 (28-81)235 (53-1469)13/22 (59%)4.5 (1-18)
    Total56% M 44% F51.5 (0-76)249 (112-1469)20/34 (59%)4 (1-32)62 (25-81)282 (53-2036)22/34 (65%)6.5 (1-48)
    • Subtotal and total results are expressed as percentage of cases (and range) for sex (male [M]/female [F]); as median (and range) for age, serum baseline tryptase (sBT), PFS, and OS; and as number of cases (and percentage) for progression and survival.

    • DBS, diffuse bone sclerosis; HEP, hepatomegaly; IDA, iron-deficiency anemia; MPN, myeloproliferative neoplasm; NEUP, neutropenia; SPLEN, splenomegaly; TRP, thrombocytopenia; +, positive; –, no progression.

    • * With organ failure.

  • Table 2.

    Number and type of genetic variants identified in purified BM MCs from SM patients by WGS (n = 4)

    Patient IDSNVsIndelsTotal variants (SNVs + indels)Mutations per Mb
    9157220.008
    10486155010.18
    13534215550.19
    1426792760.10
    Average326133390.12
    • Indels, insertions and deletions; SNV, single nucleotide variant.

  • Table 3.

    Number of genes carrying nonsynonymous coding genetic variants (somatic vs germline mutations) per SM patient grouped according to the distinct diagnostic subtypes of the disease

    Patient IDWHO diagnostic subtypeHematopoietic acquired somatic mutationsGermline genetic variants or early acquired mutationsMutations, median (range), nPatients with ≥2 mutations (%)Total genetic variantsMutations, median (range), nPatients with ≥3 mutations (%)
    MC restricted mutationsMutations, median (range), nMutated patients (%)Multilineal mutationsMutations, median (range), nMutated patients (%)Total somatic mutationsMutations, median (range), nMutated patients (%)
    1ISM0 (0-2)3/12 (25)0 (0-2)3/12 (25)0 (0-3)4/12 (33)1 (0-2)3/12 (25)1 (0-4)3/12 (25)
    2ISM1 (EP400)1
    3ISM2 (RECQL4, NSD2)2
    4ISM1 (DCC)1
    5ISM1 (ITGA10)11
    6ISM
    7ISM1 (RUNX1)12 (CSF1R, MARK4)3
    8ISM1 (SYNE1)1
    9ISM2 (IGF2R, ITPKA)2
    10ISM1 (HSP90AA1)1
    11ISM2 (EZH2, SF3B1)1 (DNMT3A)33
    12ISM1 (IKZF1)2 (ASXL1, DNMT3A)31 (DCC)4
    13ASM0 (0-1) NS2/8 (25) NS2 (0-5) P = .0047/8 (88) P = .0082 (0-5) P = .027/8 (88) P = .021 (SDHC)1 (0-6) NS3/8 (38) NS13 (1-11) P = .026/8 (75) P = .03
    14ASM1 (PIK3CD)1 (EPHA7)22
    15ASM2 (EZH2, IKZF1)21 (DST)3
    16ASM2 (SRSF2, TET2)21 (CREBBP)3
    17ASM1 (KAT6B)2 (ASXL1, RUNX1)33
    18ASM3 (EZH2, ROS1, SF3B1)33 (EPHB6, LRP1B, RPS6KA2)6
    19ASM1 (EZH2)13 (CYP2C19, LRP1B, TCF3)4
    20ASM5 (CDH11, ICK, SRSF2, RUNX1, TET2)56 (ADGRB3, MBD1, MUC1, NFKB2, NOTCH4, SOCS1)11
    • Results are expressed as number of genetic variants per case after classifying the genetic variants into hematopoietic restricted mutations and germline genetic variants or early acquired mutations (ie, during embryonic development).

    • NS, not statistically significantly different.

  • Table 4.

    SM patients: prognostic factors for PFS and OS (n = 34)

    Disease featuresnUnivariate analysis
    PFS, yOS, y
    Median (range)PMedian (range)P
    Clinical and laboratory features
     Diagnosis
      Nonadvanced SM1214 (2-32)NSNR (3-48)NS
      Advanced SM2211 (1-18)11 (1-18)
     Age at diagnosis, y
      <602314 (1-32)NSNR (1-48)NS
      ≥60115 (1-10)6 (1-12)
     Skin lesions
      No104 (1-6)NS6 (1-13)0.02
      Yes2414 (1-32)NR (3-48)
     BM MCs, %
      <1145 (1-19)NS11 (1-19)NS
      ≥11814 (1-32)NR (1-48)
     sBT, µg/L
      <2001015 (1-17)NSNR (1-17)NS
      ≥200226 (1-32)NR (1-48)
     Hemoglobin, g/L
      <10053 (1-6)NS4 (1-7).001
      ≥1002914 (1-32)NR (1-48)
     Platelets, ×109/L
      <100114 (1-15).034 (1-17).04
      ≥1002314 (1-32)NR (1-48)
     β2-microglobulin, µg/mL
      <2.57NR (2-18)NSNR (3-17).04
      ≥2.5205 (1-32)10 (1-48)
     SAP, U/L
      <1501632 (2-32).01NR (3-48).01
      ≥150144 (1-30)10 (1-39)
     Splenomegaly
      No1130 (1-30).04NR (1-39)NS
      Yes235 (1-32)11 (1-48)
     Hepatomegaly
      No1615 (1-19)NSNR (1-19)NS
      Yes185 (1-32)11 (1-48)
    Number of nonsynonymous coding genetic variants
     Total somatic mutations
      0930 (2-32).02NR (3-48).005
      ≥1114 (1-15)6 (2-17)
     MC restricted
      01514 (1-32)NSNR (2-48)NS
      ≥156 (1-15)7 (6-17)
     Multilineal
      01030 (2-32).009NR (3-48).001
      ≥1103 (1-10)6 (2-10)
     Germline genetic variants
      <31714 (1-32).016NR (4-48).004
      ≥333 (1-4)4 (2-10)
     Total genetic variants
      <31130 (2-32).002NR (3-48)<.001
      ≥393 (1-6)6 (2-10)
    Gene panel mutational status
     S/A/R
      WT2315 (2-32)<.001NR (3-48).002
      Mutated112 (1-4)6 (1-13)
     S/A/R/E
      WT1930 (2-32)<.001NR (3-48)<.001
      Mutated153 (1-6)6 (1-13)
    • NR, not reached; NS, not statistically significant (P > .05); SAP, serum alkaline phosphatase; WT, wild-type.

  • Table 5.

    SM: multivariate analyses of prognostic factors for PFS and OS for the entire patient series (n = 34)

    Disease featuresnPFSOS
    HR (95% CI)PHR (95% CI)P
    Clinical and laboratory features
     Hemoglobin, g/L
      <1005NTNS
      ≥10029
     Skin lesions
      No10NTNS
      Yes24
     Platelets, ×109/L
      <10011NSNS
      ≥10023
     β2-microglobulin, µg/mL
      <2.57NTNS
      ≥2.520
     SAP, U/L
      <15016NSNS
      ≥15014
     Splenomegaly
      No11NSNS
      Yes23
    Gene panel mutational status
    S/A/R
      WT23NSNS
      Mutated11
    S/A/R/E
      WT197.6 (2.2-2.6).00113.1 (2.7-64).001
      Mutated15
    • NS, not statistically significant (P > 0.05); NT, not tested.