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Myeloproliferative Neoplasms
Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):366-374
Molecular quantification of tissue disease burden is a new biomarker and independent predictor of survival in mastocytosis
Georg Greiner,1,2 Michael Gurbisz,1 Franz Ratzinger,1 Nadine Witzeneder,1,3 Svenja Verena Class,4 Gregor Eisenwort,2,3 Ingrid Simonitsch-Klupp,4 Harald Esterbauer,1,2 Matthias Mayerhofer,5 Leonhard Müllauer,4 Wolfgang R. Sperr,2,3 Peter Valent,2,3 and Gregor Hoermann1,2,6
1Department of Laboratory Medicine, Medical University of Vienna, Vienna; 2Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna; 3Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna; 4Department of Pathology, Medical University of Vienna, Vienna; 5Ludwig Boltzmann Institute of Osteology, Hanusch Hospital, Vienna and 6Central Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Innsbruck, Innsbruck, Austria
ABSTRACT
Ahigh allele burden of the KIT D816V mutation in peripheral blood or bone marrow aspirates indicates multi-lineage hematopoietic involvement and has been associated with an aggressive clinical course of systemic mastocytosis. Since mast cells are substantially under- represented in these liquid specimens, their mutation burden likely under- estimates the tumor burden of the disease. We used a novel previously val- idated digital polymerase chain reaction (PCR) method for KIT D816V analysis to systematically analyze the mutation burden in formalin-fixed, paraffin-embedded bone marrow tissue sections of 116 mastocytosis patients (91 with indolent and 25 with advanced systemic mastocytosis), and to evaluate for the first time the clinical value of the tissue mutation burden as a novel biomarker. The KIT D816V mutation burden in the tissue was significantly higher and correlated better with bone marrow mast cell infiltration (r=0.68 vs. 0.48) and serum tryptase levels (r=0.68 vs. 0.58) com- pared to that in liquid specimens. Furthermore, the KIT D816V tissue muta- tion burden was: (i) significantly higher in advanced than in indolent sys- temic mastocytosis (P=0.001); (ii) predicted survival of patients in multivari- ate analyses independently; and (iii) was significantly reduced after response to cytoreductive therapy. Finally, digital PCR was more sensitive in detecting KIT D816V in bone marrow sections of indolent systemic mas- tocytosis patients than melting curve analysis after peptide nucleic acid- mediated PCR clamping (97% vs. 89%; P<0.05). In summary, digital PCR- based measurement of KIT D816V mutation burden in the tissue represents a novel biomarker with independent prognostic significance that can also be employed for monitoring disease progression and treatment response in systemic mastocytosis.
Introduction
Systemic mastocytosis (SM) is a clonal hematopoietic disorder characterized by abnormal infiltration of mast cells (MC) in various organs, including the bone mar- row (BM).1 The somatic KIT D816V mutation leads to growth factor-independent activation of the receptor tyrosine kinase KIT.2,3 Detection of the mutation in the BM, peripheral blood (PB), or another extra-cutaneous organ is a minor diagnostic criteri- on for SM.1,4 Although this typical driver mutation is present in a vast majority of all patients with SM, the clinical course in SM is highly variable.5 The World Health Organization (WHO) classification divides mastocytosis into cutaneous mastocytosis (CM), indolent SM (ISM), smoldering SM (SSM), aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).1,4,6
Correspondence:
GREGOR HOERMANN
gregor.hoermann@meduniwien.ac.at
Received: January 29, 2019. Accepted: April 18, 2019. Pre-published: April 24, 2019.
doi:10.3324/haematol.2019.217950
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/366
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