Clonal evolution in myelodysplastic syndromes

Silva-Coelho, Pedro da; Kroeze, Leonie I.; Yoshida, Kenichi; Koorenhof-Scheele, Theresia N.; Knops, Ruth; Locht, Louis T. van de; Graaf, Aniek O. de; Massop, Marion; Sandmann, Sarah; Dugas, Martin; Stevens‐Kroef, Marian; Čermák, Jaroslav; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Witte, Théo de; Blijlevens, Nicole M. A.; Muus, Petra; Huls, Gerwin; Reijden, Bert A. van der; Ogawa, Seishi; Jansen, Joop H.

doi:10.1038/ncomms15099

Cited by 130 publications

(154 citation statements)

References 42 publications

(51 reference statements)

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“…5 Patient follow up also reveals a highly dynamic evolution of these mutations during disease progression in treated and untreated patients. 6,7 This observation is in line with the recent recognition that human tumors harbor an extensive genetic intratumoral heterogeneity.…”

Section: 4supporting

confidence: 73%

Single-molecule DNA sequencing of acute myeloid leukemia and myelodysplastic syndromes with multiple TP53 alterations

et al. 2017

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Section: 4supporting

confidence: 73%

Single-molecule DNA sequencing of acute myeloid leukemia and myelodysplastic syndromes with multiple TP53 alterations

et al. 2017

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“…23 Notably, selection of mutational profiles was heterogeneous with some patients having no clonal variance during several years, while other had a highly dynamic shift of their mutational profile. 22,36,37 To our knowledge, mutational selection under AZA treatment in therapy-related MDS/AML has not been explored and could have an interest in term of prognosis and prediction of response or relapse. Recently, analysis of clonal selection under AZA treatment before allogeneic stem cell transplantation (allo-SCT) 32 confirmed that AZA could select mutated clones and showed that recurrent clones could re-emerge at relapse.…”

Section: Discussionmentioning

confidence: 99%

“…Median number of cycle was 10 (range 3-15). Median OS was 15 months (range, [12][13][14][15][16][17][18][19][20][21][22].…”

Section: Correlation Between Aza Response and Putative Function Of mentioning

confidence: 99%

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Clonal selection in therapy‐related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment

Calleja

Yun

Moreilhon

et al. 2020

European J of Haematology

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Introduction Therapy‐related myelodysplastic syndrome and acute myeloid leukemia (t‐MDS/AML) are defined as complications of previous cytotoxic therapy. Azacitidine (AZA), a hypomethylating agent, has showed activity in t‐MDS/AML. Objectives We evaluated the clonal dynamics of AZA‐treated t‐MDS/AML. Methods We collected bone marrow samples, at diagnosis and during treatment, from AZA‐treated t‐MDS/AML patients. NGS on 19 myeloid genes was performed, and candidate mutations with a variant allele frequency >5% were selected. Results Seven t‐AML and 12 t‐MDS were included with median age of 71 (56‐82) years old, median number of AZA cycles of 6 (1‐15), and median overall survival (OS) of 14 (3‐29) months. We observed correlation between AZA response and clonal selection. Decrease of TP53‐mutated clone was correlated with response to AZA, confirming AZA efficacy in this subgroup. In some patients, emergence of mutations was correlated with progression or relapse without impact on OS. Clones with mutations in genes for DNA methylation regulation frequently occurred with other mutations and remained stable during AZA treatment, independent of AZA response. Conclusion We confirmed that the molecular complexity of t‐MNs and that the follow‐up of clonal selection during AZA treatment could be useful to define treatment combination.

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“…da Silva-Coelho with colleagues observed that mutational spectrum and CE are influenced by lenalidomide therapy. 49 In general, treatment may…”

Section: Microarray Analysismentioning

confidence: 99%

Cryptic aberrations may allow more accurate prognostic classification of patients with myelodysplastic syndromes and clonal evolution

Svobodova

Lhotska

Hodanova

et al. 2020

Genes Chromosomes & Cancer

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The karyotype of bone-marrow cells at the time of diagnosis is one of the most important prognostic factors in patients with myelodysplastic syndromes (MDS). In some cases, the acquisition of additional genetic aberrations (clonal evolution [CE]) associated with clinical progression may occur during the disease. We analyzed a cohort of 469 MDS patients using a combination of molecular cytogenomic methods to identify cryptic aberrations and to assess their potential role in CE. We confirmed CE in 36 (8%) patients. The analysis of bone-marrow samples with a combination of cytogenomic methods at diagnosis and after CE identified 214 chromosomal aberrations. The early genetic changes in the diagnostic samples were frequently MDS specific (17 MDS-specific/57 early changes). Most progression-related aberrations identified after CE were not MDS specific (131 non-MDS-specific/155 progressionrelated changes). Copy number neutral loss of heterozygosity (CN-LOH) was detected in 19% of patients. MDS-specific CN-LOH (4q, 17p) was identified in three patients, and probably pathogenic homozygous mutations were found in TET2 (4q24)and TP53 (17p13.1) genes. We observed a statistically significant difference in overall survival (OS) between the groups of patients divided according to their diagnostic cytogenomic findings, with worse OS in the group with complex karyotypes (P = .021). A combination of cytogenomic methods allowed us to detect many cryptic genomic changes and identify genes and genomic regions that may represent therapeutic targets in patients with progressive MDS.

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Clonal evolution in myelodysplastic syndromes

Cited by 130 publications

References 42 publications

Single-molecule DNA sequencing of acute myeloid leukemia and myelodysplastic syndromes with multiple TP53 alterations

Single-molecule DNA sequencing of acute myeloid leukemia and myelodysplastic syndromes with multiple TP53 alterations

Clonal selection in therapy‐related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment

Cryptic aberrations may allow more accurate prognostic classification of patients with myelodysplastic syndromes and clonal evolution

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