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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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Comparison of variant allele frequencies across tier 1 somatic single nucleotide variants (SNVs)The variant allele frequency for each tier 1 SNV across the PMF, sAML, and sAML remission/relapsed PMF samples is shown. The genes with the SNVs are divided based on whether the SNV was present predominantly in all three samples (Shared SNVs), only the PMF sample (PMF SNVs), low in the PMF sample but high in sAML and sAML remission/relapsed PMF samples (Low PMF SNVs), and only in the sAML sample (sAML SNVs).
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Figure 2: Comparison of variant allele frequencies across tier 1 somatic single nucleotide variants (SNVs)The variant allele frequency for each tier 1 SNV across the PMF, sAML, and sAML remission/relapsed PMF samples is shown. The genes with the SNVs are divided based on whether the SNV was present predominantly in all three samples (Shared SNVs), only the PMF sample (PMF SNVs), low in the PMF sample but high in sAML and sAML remission/relapsed PMF samples (Low PMF SNVs), and only in the sAML sample (sAML SNVs).

Mentions: A total of 38 tier 1 SNVs were validated across the three tumor samples (Figure 2, Supplementary Table 3). Of the validated tier 1 SNVs, six were identified as putative driver mutations (JAK2, U2AF1, MYB, ASXL1, RUNX1, IDH1) based on prior studies demonstrating mutations in each of these genes in MPNs and/or sAML (Table 2).(20, 48-51) The JAK2 and U2AF1 mutations were identified in all three samples with a variant allele frequency (VAF) of approximately 75% and 40%, respectively. The MYB mutation was present in the PMF sample at a VAF of 20%, but was not detectable in the sAML or sAML remission/relapsed PMF samples. A mutation in ASXL1 was found at a low frequency (6%) in the PMF sample, but was substantially enriched in the sAML (44%) and sAML remission/relapsed PMF (32%) samples. RUNX1 and IDH1 mutations were validated only in the sAML sample at VAFs of 35 and 30%, respectively. Amongst the remaining 32 tier 1 SNVs, a mutation in the HCFC1 gene was identified as an additional possible driver based on its expression, known function and interaction in pathways also involving ASXL1.(52-54) This mutation followed a VAF pattern across the three different disease stages that was quite similar to ASXL1, suggesting a possible synergy between the two mutations.


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)

Comparison of variant allele frequencies across tier 1 somatic single nucleotide variants (SNVs)The variant allele frequency for each tier 1 SNV across the PMF, sAML, and sAML remission/relapsed PMF samples is shown. The genes with the SNVs are divided based on whether the SNV was present predominantly in all three samples (Shared SNVs), only the PMF sample (PMF SNVs), low in the PMF sample but high in sAML and sAML remission/relapsed PMF samples (Low PMF SNVs), and only in the sAML sample (sAML SNVs).
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Related In: Results  -  Collection

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Figure 2: Comparison of variant allele frequencies across tier 1 somatic single nucleotide variants (SNVs)The variant allele frequency for each tier 1 SNV across the PMF, sAML, and sAML remission/relapsed PMF samples is shown. The genes with the SNVs are divided based on whether the SNV was present predominantly in all three samples (Shared SNVs), only the PMF sample (PMF SNVs), low in the PMF sample but high in sAML and sAML remission/relapsed PMF samples (Low PMF SNVs), and only in the sAML sample (sAML SNVs).
Mentions: A total of 38 tier 1 SNVs were validated across the three tumor samples (Figure 2, Supplementary Table 3). Of the validated tier 1 SNVs, six were identified as putative driver mutations (JAK2, U2AF1, MYB, ASXL1, RUNX1, IDH1) based on prior studies demonstrating mutations in each of these genes in MPNs and/or sAML (Table 2).(20, 48-51) The JAK2 and U2AF1 mutations were identified in all three samples with a variant allele frequency (VAF) of approximately 75% and 40%, respectively. The MYB mutation was present in the PMF sample at a VAF of 20%, but was not detectable in the sAML or sAML remission/relapsed PMF samples. A mutation in ASXL1 was found at a low frequency (6%) in the PMF sample, but was substantially enriched in the sAML (44%) and sAML remission/relapsed PMF (32%) samples. RUNX1 and IDH1 mutations were validated only in the sAML sample at VAFs of 35 and 30%, respectively. Amongst the remaining 32 tier 1 SNVs, a mutation in the HCFC1 gene was identified as an additional possible driver based on its expression, known function and interaction in pathways also involving ASXL1.(52-54) This mutation followed a VAF pattern across the three different disease stages that was quite similar to ASXL1, suggesting a possible synergy between the two mutations.

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