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