Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms

Abstract

Mutations in isocitrate dehydrogenase 1/2 (IDH1/2 MT) are drivers of a variety of myeloid neoplasms. As they yield the same oncometabolite, D-2-hydroxyglutarate, they are often treated as equivalent, and pooled. We studied the validity of this approach and found IDH1/2 mutations in 179 of 2119 myeloid neoplasms (8%). Cross-sectionally, the frequencies of these mutations increased from lower- to higher risk disease, thus suggesting a role in clinical progression. Variant allelic frequencies indicated that IDH1 MT and IDH2 MT are ancestral in up to 14/74 (19%) vs 34/99 (34%; P=0.027) of cases, respectively, illustrating the pathogenic role of these lesions in myeloid neoplasms. IDH1/2 MT was associated with poor overall survival, particularly in lower risk myelodysplastic syndromes. Ancestral IDH1 MT cases were associated with a worse prognosis than subclonal IDH1 MT cases, whereas the position of IDH2 MT within clonal hierarchy did not impact survival. This may relate to distinct mutational spectra with more DNMT3A and NPM1 mutations associated with IDH1 MT cases, and more ASXL1, SRSF2, RUNX1, STAG2 mutations associated with IDH2 MT cases. Our data demonstrate important clinical and biological differences between IDH1 MT and IDH2 MT myeloid neoplasms. These mutations should be considered separately as their differences could have implications for diagnosis, prognosis and treatment with IDH1/2 MT inhibitors of IDH1/2 MT patients.