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

Abstract

Systemic mastocytosis (SM) is a highly heterogeneous disease with indolent and aggressive forms, with the mechanisms leading to malignant transformation still remaining to be elucidated. Here, we investigated the presence and frequency of genetic variants in 34 SM patients with multilineal KIT D816V mutations. Initial screening was performed by targeted sequencing of 410 genes in DNA extracted from purified bone marrow cells and hair from 12 patients with nonadvanced SM and 8 patients with advanced SM, followed by whole-genome sequencing (WGS) in 4 cases. Somatic mutations were further investigated in another 14 patients with advanced SM. Despite the fact that no common mutation other than KIT D816V was found in WGS analyses, targeted next-generation sequencing identified 67 nonsynonymous genetic variants involving 39 genes. Half of the mutations were somatic (mostly multilineal), whereas the other half were germline variants. The presence of ≥1 multilineal somatic mutation involving genes other than KIT D816V, ≥3 germline variants, and ≥1 multilineal mutation in the SRSF2, ASXL1, RUNX1, and/or EZH2 genes (S/A/R/E genes), in addition to skin lesions, splenomegaly, thrombocytopenia, low hemoglobin levels, and increased alkaline phosphatase and β2-microglobulin serum levels, were associated with a poorer patient outcome. However, the presence of ≥1 multilineal mutation, particularly involving S/A/R/E genes, was the only independent predictor for progression-free survival and overall survival in our cohort.

MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis

“… 10 , 11 Recent data, however, have highlighted that the molecular landscape of AdvSM is complex, with at least one somatic mutation in addition to KIT D816V (eg, in ASXL1 , CBL , JAK2 , RUNX1 , SRSF2 , or TET2 ) being present in more than 60% of patients with AdvSM. 12 , 13 In more recent studies, several groups examined the prognostic impact of these mutations. The presence and number of additional molecular mutations, notably in SRSF2 , ASXL , and/or RUNX1 (S/A/R), have a strong adverse influence on progression (leukemic transformation) to secondary MCL and/or secondary acute myeloid leukemia (AML), response to treatment, and OS.…”

Systemic mastocytosis with chronic myelomonocytic leukemia followed by transformation into acute myeloid leukemia

“…Karyotype abnormalities were detected in 32% patients with SM-AHN but rarely in patients with ASM [14,15]. The abnormalities were most often found in patients with SM-AML [7].…”

Systemic Mastocytosis: Following the Tyrosine Kinase Inhibition Roadmap

“…By contrast, a few patients with AdvSM show a more favorable clinical behavior with prolonged survival rates. Recent investigations have suggested that the absence of mutations in genes other than KIT including SRSF2, ASXL1, RUNX1, and EZH2 might be associated with better prognosis in terms of OS in patients with AdvSM (Jawhar et al, 2016;Muñoz-González et al, 2018).…”