NGS Testing Practices and Molecular Profile Landscape of the KIT Gene in Systemic Mastocytosis: Real-World Insights from Selected European Countries

Background: Globally, over 90% of adult systemic mastocytosis (SM) cases are associated with somatic gain-of-function point mutations in the KIT gene, mainly KIT D816V mutations (Lim, Blood 2009;113:5727-5736; Garcia-Montero, Blood 2006;108:2366-2372). However, little is known about the molecular profile characterization of the KIT gene in European patients with SM, and the co-occurrence of somatic variants in other genes such as SRSF2, ASXL1, TET2, SRSF2, ASXL1, and RUNX1. Such co-mutations can underly disease phenotype as well as impact prognosis and treatment strategy (Jawhar, Leukemia 2015;30:136-143; Schwaab, Blood 2013;122:2460-2466). This study describes the landscape of next-generation sequencing (NGS) testing in clinical practice for KIT mutations in selected European countries (France, Italy, Germany, and Spain). It also provides evidence on the epidemiologic distribution of additional myeloid/myeloproliferative malignancy genes of interest other than KIT. These findings could have implications for SM testing and treatment strategies.

Methods: We conducted a retrospective study (Q1 2019-Q2 2021) using pseudo-anonymized real-world genomic profiles from 59 Institutions using the SOPHiA DDM™ platform (SOPHiA GENETICS SA, Switzerland). The platform was used to analyze data from somatic oncology NGS panels (including 34 onco-hematological [HemOnc] panels) capable of detecting KIT alterations from RNA or DNA samples. Genomic data were processed by the SOPHiA GENETICS proprietary algorithms that support the detection and annotation of multiple variant classes.

Results: Out of the 78,410 somatic oncology NGS test samples analyzed in this study, 40.9% were tested with somatic HemOnc panels capable of detecting KIT alterations. Of those tested with HemOnc panels, a total of 33,289 KIT gene variants were identified amongst 12,840 KIT mutation-positive patients. Of the KIT mutation-positive patients, 258 (2.01%) had a KIT D816V mutation, and in the majority (approximately 85%) of these cases, the KIT D816V mutation was associated with a myeloid/myeloproliferative malignancy. The co-occurrence and mutual exclusivity analysis of KIT drivers within KIT or other genes found that 126 (48.8%) of KIT D816V mutation-positive patients had at least one co-occurring oncogenic alteration in the other investigated genes (KIT, SRSF2, ASXL1, TET2, and RUNX1). Finally, we observed that seven KIT D816V mutation-positive patients (2.7%) showed intratumoral heterogeneity for KIT D816 variants, which could reflect a subclonal architecture of the tumors.

Conclusions: This study provides new insights into the occurrence of KIT alterations and concurrent presence of co-mutations in systemic mastocytosis patients, and how specific somatic NGS applications, namely HemOnc panels, are used across France, Italy, Germany, and Spain. The comprehensive characterization of the molecular epidemiology of KIT variants and co-mutations is crucial to better define SM prognosis and treatment strategies. More research is needed to determine the implications of these findings.

Lamontagne:Blueprint Medicines: Current Employment, Current equity holder in publicly-traded company. Cheloni:SOPHiA GENETICS: Current Employment, Current equity holder in publicly-traded company. Lima:SOPHiA GENETICS: Current Employment, Current equity holder in publicly-traded company. Cettou:SOPHiA GENETICS: Current Employment, Current equity holder in publicly-traded company. Green:Blueprint Medicines: Current Employment, Current equity holder in publicly-traded company. Crouch:Blueprint Medicines: Current Employment, Current equity holder in publicly-traded company. Kim:Blueprint Medicines: Current Employment, Current equity holder in publicly-traded company.