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

2015; Springer Nature; Volume: 29; Issue: 11 Linguagem: Inglês

10.1038/leu.2015.91

1476-5551

Remco J. Molenaar, Swapna Thota, Yasunobu Nagata, Bhumika J. Patel, Michael J. Clemente, Bartlomiej Przychodzen, Cassandra Hirsh, Aaron D. Viny, N Hosano, Fonnet E. Bleeker, Manja Meggendorfer, Tamara Alpermann, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Cornelis J.F. Van Noorden, Tomas Radivoyevitch, Hetty E. Carraway, Hideki Makishima, Satoru Miyano, Mikkael A. Sekeres, Seishi Ogawa, Torsten Haferlach, Jaroslaw P. Maciejewski,

Cancer Genomics and Diagnostics

Mutations in isocitrate dehydrogenase 1/2 (IDH1/2MT) 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 IDH1MT and IDH2MT 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. IDH1/2MT was associated with poor overall survival, particularly in lower risk myelodysplastic syndromes. Ancestral IDH1MT cases were associated with a worse prognosis than subclonal IDH1MT cases, whereas the position of IDH2MT within clonal hierarchy did not impact survival. This may relate to distinct mutational spectra with more DNMT3A and NPM1 mutations associated with IDH1MT cases, and more ASXL1, SRSF2, RUNX1, STAG2 mutations associated with IDH2MT cases. Our data demonstrate important clinical and biological differences between IDH1MT and IDH2MT myeloid neoplasms. These mutations should be considered separately as their differences could have implications for diagnosis, prognosis and treatment with IDH1/2MT inhibitors of IDH1/2MT patients.