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.
