The different variant allele frequencies of type I/type II mutations and the distinct molecular landscapes in CALR-mutant essential thrombocythaemia and primary myelofibrosis

Abstract

ABSTRACT Objective Calreticulin (CALR) mutations have been identified as driver mutations in a quarter of patients with essential thrombocythaemia (ET) and primary myelofibrosis (PMF), which are subgroups of myeloproliferative neoplasms (MPNs). A 52-bp deletion (type I mutation) and a 5-bp insertion (type II mutation) are the most frequent variants. To better understand the impact of different CALR mutant variants, with or without nondriver mutations, on the clinical subtypes of MPN needs further investigation. Methods The clinical characteristics, laboratory parameters and genetic mutation statuses were analysed in a cohort of 77 MPN patients with CALR mutations (ET = 24, prePMF = 33, and overt PMF = 20). Targeted NGS using a 38-gene panel was performed to evaluate the variant allele frequency (VAF) of CALR type I/type II mutations and assess the molecular landscape of nondriver gene mutations. Results A lower VAF of type I vs. type II was observed in CALR-mutant ET, prePMF and overt PMF, and a higher frequency of type I vs. type II was found in CALR-mutant overt PMF. Additional somatic mutations were indicated to be useful in understanding the pathogenesis of MPN. In this study, the mutation landscape was more complex in overt PMF than in ET or in prePMF. Mutations in epigenetic regulators (ASXL1, EZH2 and TET2) were more common in overt PMF. Conclusions The two different subtypes of CALR mutations may have different impacts on MPN. A lower VAF of CALR type I indicates a greater contribution to disease progression in MPN, and increased nondriver mutations may be important in myelofibrosis progression.