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Comprehensive mutational profiling in advanced systemic mastocytosis

Comprehensive mutational profiling in advanced systemic mastocytosis
Comprehensive mutational profiling in advanced systemic mastocytosis
To explore mechanisms contributing to the clinical heterogeneity of systemic mastocytosis (SM) and to suboptimal responses to diverse therapies, we analyzed 39 KIT D816V mutated patients with indolent SM (ISM, n=10), smoldering SM (SSM, n=2), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5), and aggressive SM (ASM, n=15) or mast cell leukemia (MCL, n=7) with (n=18) or without (n=4) AHNMD for additional molecular aberrations. We applied next-generation sequencing to investigate ASXL1, CBL, IDH1/2, JAK2, KRAS, MLL-PTD, NPM1, NRAS, TP53, SRSF2, SF3B1, SETBP1, U2AF1 at mutational hotspot regions, and analyzed complete coding regions of EZH2, ETV6, RUNX1 and TET2. We identified additional molecular aberrations in 24/27 (89%) patients with advanced SM (SM-AHNMD, 5/5; ASM/MCL, 19/22) while only 3/12 (25%) ISM/SSM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (p<0.001). Most frequently affected genes were TET2, SRSF2, ASXL1, CBL and RUNX1. In advanced SM, 21/27 patients (78%) carried ?3 mutations and 11/27 patients (41%) exhibited ?5 mutations. Overall survival was significantly shorter in patients with additional aberrations as compared to those with KIT D816V only (p=0.019). We conclude that biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution.
0006-4971
2460-2466
Schwaab, Juliana
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Schnittger, Susanne
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Sotlar, Karl
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Walz, Christoph
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Fabarius, Alice
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Pfirrmann, Markus
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Kohlmann, Alexander
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Grossmann, Vera
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Meggendorfer, Manja
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Horny, Hans-Peter
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Valent, Peter
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Jawhar, Mohamad
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Teichmann, Martina
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Metzgeroth, Georgia
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Erben, Philipp
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Ernst, Thomas
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Hochhaus, Andreas
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Haferlach, Torsten
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Hofmann, Wolf-Karsten
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Cross, Nicholas C.P.
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Reiter, Andreas
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Schwaab, Juliana
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Schnittger, Susanne
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Sotlar, Karl
e3e96797-3fab-4c37-8728-7c77bb3ba389
Walz, Christoph
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Fabarius, Alice
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Pfirrmann, Markus
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Kohlmann, Alexander
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Grossmann, Vera
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Meggendorfer, Manja
3e6a7136-7586-4220-8c3c-512e0c872f2d
Horny, Hans-Peter
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Valent, Peter
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Jawhar, Mohamad
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Teichmann, Martina
442c1152-a8d8-470f-a056-4be94bb4efb8
Metzgeroth, Georgia
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Erben, Philipp
defa0bda-e318-499b-9f62-36288a8407ae
Ernst, Thomas
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Hochhaus, Andreas
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Haferlach, Torsten
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Hofmann, Wolf-Karsten
ab66838b-bf8c-4352-a0f0-3c8aafed2570
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Reiter, Andreas
ffa23e84-4a13-4cb5-aaf0-3fafe25dbede

Schwaab, Juliana, Schnittger, Susanne, Sotlar, Karl, Walz, Christoph, Fabarius, Alice, Pfirrmann, Markus, Kohlmann, Alexander, Grossmann, Vera, Meggendorfer, Manja, Horny, Hans-Peter, Valent, Peter, Jawhar, Mohamad, Teichmann, Martina, Metzgeroth, Georgia, Erben, Philipp, Ernst, Thomas, Hochhaus, Andreas, Haferlach, Torsten, Hofmann, Wolf-Karsten, Cross, Nicholas C.P. and Reiter, Andreas (2013) Comprehensive mutational profiling in advanced systemic mastocytosis. Blood, 122 (14), 2460-2466. (doi:10.1182/blood-2013-04-496448). (PMID:23958953)

Record type: Article

Abstract

To explore mechanisms contributing to the clinical heterogeneity of systemic mastocytosis (SM) and to suboptimal responses to diverse therapies, we analyzed 39 KIT D816V mutated patients with indolent SM (ISM, n=10), smoldering SM (SSM, n=2), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5), and aggressive SM (ASM, n=15) or mast cell leukemia (MCL, n=7) with (n=18) or without (n=4) AHNMD for additional molecular aberrations. We applied next-generation sequencing to investigate ASXL1, CBL, IDH1/2, JAK2, KRAS, MLL-PTD, NPM1, NRAS, TP53, SRSF2, SF3B1, SETBP1, U2AF1 at mutational hotspot regions, and analyzed complete coding regions of EZH2, ETV6, RUNX1 and TET2. We identified additional molecular aberrations in 24/27 (89%) patients with advanced SM (SM-AHNMD, 5/5; ASM/MCL, 19/22) while only 3/12 (25%) ISM/SSM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (p<0.001). Most frequently affected genes were TET2, SRSF2, ASXL1, CBL and RUNX1. In advanced SM, 21/27 patients (78%) carried ?3 mutations and 11/27 patients (41%) exhibited ?5 mutations. Overall survival was significantly shorter in patients with additional aberrations as compared to those with KIT D816V only (p=0.019). We conclude that biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution.

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More information

e-pub ahead of print date: 19 August 2013
Published date: 3 October 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 356048
URI: http://eprints.soton.ac.uk/id/eprint/356048
ISSN: 0006-4971
PURE UUID: e9850111-0cef-4e2b-9940-954a38491e23
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 10 Sep 2013 12:33
Last modified: 28 Apr 2022 01:49

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Contributors

Author: Juliana Schwaab
Author: Susanne Schnittger
Author: Karl Sotlar
Author: Christoph Walz
Author: Alice Fabarius
Author: Markus Pfirrmann
Author: Alexander Kohlmann
Author: Vera Grossmann
Author: Manja Meggendorfer
Author: Hans-Peter Horny
Author: Peter Valent
Author: Mohamad Jawhar
Author: Martina Teichmann
Author: Georgia Metzgeroth
Author: Philipp Erben
Author: Thomas Ernst
Author: Andreas Hochhaus
Author: Torsten Haferlach
Author: Wolf-Karsten Hofmann
Author: Andreas Reiter

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