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. 2015 Nov;29(11):2134-42.
doi: 10.1038/leu.2015.91. Epub 2015 Apr 3.

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

R J Molenaar  1   2 , S Thota  1 , Y Nagata  3 , B Patel  1 , M Clemente  1 , B Przychodzen  1 , C Hirsh  1 , A D Viny  4 , N Hosano  1 , F E Bleeker  5 , M Meggendorfer  6 , T Alpermann  6 , Y Shiraishi  7 , K Chiba  7 , H Tanaka  8 , C J F van Noorden  2 , T Radivoyevitch  9 , H E Carraway  10 , H Makishima  1 , S Miyano  3 , M A Sekeres  1   10 , S Ogawa  3 , T Haferlach  6 , J P Maciejewski  1
Affiliations

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

R J Molenaar et al. Leukemia. 2015 Nov.

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.

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Conflict of interest statement

Conflict of interest:

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Breakdown of IDH1/2 mutations among disease types and specific amino acid substitutions
(A) Frequencies of IDH1 and IDH2 mutations in various myeloid neoplasms. (B) Pie chart showing the percentages of the specific IDH1/2 mutational amino acid substitutions in the cohort. Abbreviations: pAML, primary acute myeloid leukemia; sAML, secondary acute myeloid leukemia.
Figure 2
Figure 2. Mutational spectrum and most and least frequently co-occurring mutations in IDH1/2-mutated cases
(A) Mutational spectrum and clinical spectrum of IDH1MT cases (left half) and IDH2MT cases (right half) with myeloid neoplasms. (B) Prevalence of co-occurring mutations in IDH1/2MT cases, compared with IDH1/2WT cases. Abbreviations: lrMDS, low-risk MDS; hrMDS, high-risk MDS; sAML, secondary acute myeloid leukemia; MDS/MPN, myelodysplastic syndromes/myeloproliferative neoplasms; pAML, primary acute myeloid leukemia; smut, somatic mutation; del, deletion; hemimut, hemizygous mutation.
Figure 3
Figure 3. Analysis of clonal architecture of IDH1/2-mutated cases
(A) Percentages of IDH1/2MT cases in which the IDH1/2 mutation was an ancestral event, a subclonal event or an event of undeterminable ancestry, based on the variant allelic frequency of the IDH1/2 mutations and other co-occurring mutations. (B) As in (A), but with specific IDH1/2 amino acid substitutions. (C) Mean variant allelic frequencies of IDH1 mutations and IDH2 mutations in IDH1/2MT cases in which the IDH1/2 mutation is an ancestral or subclonal event, or of undeterminable ancestry. (D) Fish plots of serially sequenced IDH1/2MT patients.
Figure 4
Figure 4. IDH1/2 mutations and associations with overall patient survival in myeloid neoplasms
(A) Survival data of IDH1/2MT patients with myeloid neoplasms. (B-E) Subset survival analyses in low-risk MDS (B), high-risk MDS (C), secondary AML (D) and primary AML (E). (F) Survival data of IDH1MT patients with myeloid neoplasms, stratified on the ancestral importance of the IDH1 mutation. (G) as in (F), but with IDH2 mutations. (H) Subset survival analysis in low-risk MDS patients, with IDH1 and IDH2 mutations shown separately. (I) As in (F), but with IDH1 mutations in low-risk MDS patients. Abbreviations: 1°, ancestral genetic event; 2°, subclonal genetic event; ?°, genetic event of undeterminable ancestry.
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References

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