Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis

Abstract

Systemic mastocytosis (SM) is a rare clonal haematopoietic stem cell disease in which activating KIT mutations (most commonly KIT D816V) are present in virtually every (>90%) adult patient at similar frequencies among non-advanced and advanced forms of SM. The KIT D816V mutation is considered the most common pathogenic driver of SM. Acquisition of this mutation early during haematopoiesis may cause multilineage involvement of haematopoiesis by KIT D816V, which has been associated with higher tumour burden and additional mutations in other genes, leading to an increased rate of transformation to advanced SM. Thus, among other mutations, alterations in around 30 genes that are also frequently mutated in other myeloid neoplasms have been reported in SM cases. From these genes, 12 (i.e., ASXL1, CBL, DNMT3A, EZH2, JAK2, KRAS, NRAS, SF3B1, RUNX1, SF3B1, SRSF2, TET2) have been recurrently reported to be mutated in SM. Because of all the above, assessment of multilineage involvement of haematopoiesis by the KIT D816V mutation, in the setting of multi-mutated haematopoiesis as revealed by a limited panel of genes (i.e., ASXL1, CBL, DNMT3A, EZH2, NRAS, RUNX1 and SRSF2) and associated with a poorer patient outcome, has become of great help to identify SM patients at higher risk of disease progression and/or poor survival who could benefit from closer follow-up and eventually also early cytoreductive treatment.

Poor Applicability of Currently Available Prognostic Scoring Systems for Prediction of Outcome in KIT D816V-Negative Advanced Systemic Mastocytosis

“…SM. It has been primarily associated with MCL, WDSM and MCS [18]. Alternative mutations in KIT are recurrently identified at position 816, e.g., D816H, D816N or D816Y [12,19].…”

“…Alternative mutations in KIT are recurrently identified at position 816, e.g., D816H, D816N or D816Y [12,19]. In isolated cases, other acquired imatinib-resistant mutations have been identified in coding regions of TK domains 1 and 2 (exons 13 to 18), e.g., I817V in WDSM, D820G in ASM and N822K in SM-AHN [18]. Potentially imatinib-sensitive mutations between exons 8 and 10 may correspond to germline mutations, e.g., S451C, K509I or F522C, which often show a familial aggregation pattern [20][21][22][23][24][25][26][27].…”

The international consensus classification of eosinophilic disorders and systemic mastocytosis

“…In contrast to ISM and SSM, the genetic profile of AdvSM is more complex, with 60%–70% of cases showing mutations in addition to KIT 130,141–145 . These additional somatic mutations are strikingly similar to those encountered in various myeloid neoplasms such as SRSF2 , ASXL1 , RUNX1 , TET2 , DNMT3A , JAK2 , CBL , and NRAS .…”

KIT Mutations and Other Genetic Defects in Mastocytosis

“…[46][47][48][49] However, other molecular aberrations repeatedly reported in patients with AdvSM, mostly in SM-AHN and to a lesser extent in ASM and MCL, 7,50-55 may affect signaling molecules (eg, CBL, KRAS, or NRAS), transcription factors (eg, RUNX1), epigenetic regulators (eg, ASXL1, DNMT3A, EZH2, or TET2), splicing factors (eg, SRSF2, SF3B1, or U2AF1) (reviewed in ref. 56 ) or the tumor suppressor SETD2. 57 Several groups have investigated the prognostic relevance of these additional mutations.…”