Comprehensive mutational profiling in advanced systemic mastocytosis

被引：212

作者：

Schwaab, Juliana ^{[1
]}

Schnittger, Susanne ^{[2
]}

Sotlar, Karl ^{[3
]}

Walz, Christoph ^{[3
]}

Fabarius, Alice ^{[1
]}

Pfirrmann, Markus ^{[4
]}

Kohlmann, Alexander ^{[2
]}

Grossmann, Vera ^{[2
]}

Meggendorfer, Manja ^{[2
]}

Horny, Hans-Peter ^{[3
]}

Valent, Peter ^{[5
,6
]}

Jawhar, Mohamad ^{[1
]}

Teichmann, Martina ^{[1
]}

Metzgeroth, Georgia ^{[1
]}

Erben, Philipp ^{[1
]}

Ernst, Thomas ^{[7
]}

Hochhaus, Andreas ^{[7
]}

Haferlach, Torsten ^{[2
]}

Hofmann, Wolf-Karsten ^{[1
]}

Cross, Nicholas C. P. ^{[8
,9
]}

Reiter, Andreas ^{[1
]}

机构：

[1] Univ Med Mannheim, Med Klin 3, D-68167 Mannheim, Germany

[2] Munich Leukemia Lab, Munich, Germany

[3] Univ Munich, Pathol Inst Munich, Munich, Germany

[4] Univ Munich, Inst Med Informat Verarbeitung Biometrie & Epidem, Munich, Germany

[5] Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Vienna, Austria

[6] Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, Vienna, Austria

[7] Univ Klinikum Jena, Abt Hamatol Onkol, Klin Innere Med 2, Jena, Germany

[8] Wessex Reg Genet Lab, Salisbury, Wilts, England

[9] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England

来源：

BLOOD | 2013年 / 122卷 / 14期

关键词：

CHRONIC MYELOMONOCYTIC LEUKEMIA; KINASE INHIBITOR; TET2; MUTATIONS; KIT; KITD816V; D816V; JAK2; ACTIVATION; DASATINIB; REVEALS;

D O I：

10.1182/blood-2013-04-496448

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 (n = 10), smoldering SM (n = 2), SM with associated clonal hematologic nonmast cell lineage disorder (SM-AHNMD, n = 5), and aggressive SM (n = 15) ormast cell leukemia (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; aggressive SM/mast cell leukemia, 19/22) whereas only 3/12 (25%) indolent SM/smoldering SM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (P < .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 = .019). We conclude that biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution.

引用

页码：2460 / 2466

页数：7

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