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Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia.

Engle EK, Fisher DA, Miller CA, McLellan MD, Fulton RS, Moore DM, Wilson RK, Ley TJ, Oh ST - Leukemia (2014)

Bottom Line: The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression.The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF.Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Washington University School of Medicine, St Louis, MO, USA.

ABSTRACT
Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single-nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

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Related in: MedlinePlus

Spectrum of transition and transversion mutations per sampleThe percentage of somatic single nucleotide variants (SNVs) in the PMF, sAML, or specific for the sAML sample are categorized by transition and transversion mutation types.
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Figure 1: Spectrum of transition and transversion mutations per sampleThe percentage of somatic single nucleotide variants (SNVs) in the PMF, sAML, or specific for the sAML sample are categorized by transition and transversion mutation types.

Mentions: An increased proportion of transversion mutations may be indicative of therapy-related DNA changes.(23, 47) For the PMF and sAML samples, the transition and transversion frequencies were roughly similar to previously published studies of AML, MDS, and MPNs (Figure 1).(22, 23, 43) sAML-specific mutations from the patient examined in this study also had a similar distribution. These findings indicate that there was no obvious therapy-related effect on mutation distribution in this case.


Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia.

Engle EK, Fisher DA, Miller CA, McLellan MD, Fulton RS, Moore DM, Wilson RK, Ley TJ, Oh ST - Leukemia (2014)

Spectrum of transition and transversion mutations per sampleThe percentage of somatic single nucleotide variants (SNVs) in the PMF, sAML, or specific for the sAML sample are categorized by transition and transversion mutation types.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4374044&req=5

Figure 1: Spectrum of transition and transversion mutations per sampleThe percentage of somatic single nucleotide variants (SNVs) in the PMF, sAML, or specific for the sAML sample are categorized by transition and transversion mutation types.
Mentions: An increased proportion of transversion mutations may be indicative of therapy-related DNA changes.(23, 47) For the PMF and sAML samples, the transition and transversion frequencies were roughly similar to previously published studies of AML, MDS, and MPNs (Figure 1).(22, 23, 43) sAML-specific mutations from the patient examined in this study also had a similar distribution. These findings indicate that there was no obvious therapy-related effect on mutation distribution in this case.

Bottom Line: The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression.The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF.Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Washington University School of Medicine, St Louis, MO, USA.

ABSTRACT
Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single-nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

Show MeSH
Related in: MedlinePlus