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.

• Authors: R J Molenaar, S Thota, Y Nagata, B Patel, M Clemente, B Przychodzen, C Hirsh, A D Viny, N Hosano, F E Bleeker, M Meggendorfer, T Alpermann, Y Shiraishi, K Chiba, H Tanaka, C J F van Noorden, T Radivoyevitch, H E Carraway, H Makishima, S Miyano, M A Sekeres, S Ogawa, T Haferlach, J P Maciejewski
• Journal: Leukemia (Leukemia) Vol. 29 Issue 11 Pg. 2134-42 (Nov 2015) ISSN: 1476-5551 [Electronic] England
• PMID: 25836588 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• NPM1 protein, human
• Proto-Oncogene Proteins
• Nucleophosmin
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human
• Dioxygenases
• TET2 protein, human

Topics

• Aged
• DNA-Binding Proteins (antagonists & inhibitors, genetics)
• Dioxygenases
• Female
• Humans
• Isocitrate Dehydrogenase (genetics)
• Leukemia, Myeloid, Acute (genetics, mortality)
• Male
• Middle Aged
• Mutation
• Myelodysplastic Syndromes (genetics, mortality)
• Nucleophosmin
• Prognosis
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics)