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Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia.

Mar BG, Bullinger LB, McLean KM, Grauman PV, Harris MH, Stevenson K, Neuberg DS, Sinha AU, Sallan SE, Silverman LB, Kung AL, Lo Nigro L, Ebert BL, Armstrong SA - Nat Commun (2014)

Bottom Line: Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples.Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort.We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.

ABSTRACT
Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signalling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.

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Relapsed B-ALL is enriched for mutations in epigenetic regulatorsA) Gain or loss of somatic mutations in matched diagnosis-relapse samples from 30 pediatric B-ALL patients. Clonal mutations at relapse which were detected in a minor subclone at diagnosis and clonal mutations at diagnosis which became subclonal at relapse are shaded. MLL: MLL rearranged, HYPO: Hypodiploidy, iAMP21: intrachromosomal amplification of chromosome 21, HYPER: Hyperdiploidy. B) Comparison of the number of patients which gain, lose, or have the same number of mutations in epigenetic regulators and signaling factors at relapse. The McNemar test was used to calculate the P-values.
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Figure 4: Relapsed B-ALL is enriched for mutations in epigenetic regulatorsA) Gain or loss of somatic mutations in matched diagnosis-relapse samples from 30 pediatric B-ALL patients. Clonal mutations at relapse which were detected in a minor subclone at diagnosis and clonal mutations at diagnosis which became subclonal at relapse are shaded. MLL: MLL rearranged, HYPO: Hypodiploidy, iAMP21: intrachromosomal amplification of chromosome 21, HYPER: Hyperdiploidy. B) Comparison of the number of patients which gain, lose, or have the same number of mutations in epigenetic regulators and signaling factors at relapse. The McNemar test was used to calculate the P-values.

Mentions: Sequencing of the 30 matched relapsed samples showed a striking gain of mutations in epigenetic regulators, with 17 (57%) harboring a mutation. Of the 11 patients that gained a mutation in an epigenetic regulator at the time of relapse, only three were detectable in a rare subclone at diagnosis. (Fig 4A). As noted above, this frequency is comparable to other poor prognosis de novo ALL subgroups such as hypodiploid and ETP ALL. In addition to the 11 gains, five patients retained the same mutations from diagnosis, and one patient had their clonal mutation reduced to a subclonal allele frequency at relapse (Supplementary Fig. 1B). Details of each identified somatic mutation in each patient and a summary of mutations by molecular subtype are available in the supplemental materials (Supplementary Tables 3 and 4).


Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia.

Mar BG, Bullinger LB, McLean KM, Grauman PV, Harris MH, Stevenson K, Neuberg DS, Sinha AU, Sallan SE, Silverman LB, Kung AL, Lo Nigro L, Ebert BL, Armstrong SA - Nat Commun (2014)

Relapsed B-ALL is enriched for mutations in epigenetic regulatorsA) Gain or loss of somatic mutations in matched diagnosis-relapse samples from 30 pediatric B-ALL patients. Clonal mutations at relapse which were detected in a minor subclone at diagnosis and clonal mutations at diagnosis which became subclonal at relapse are shaded. MLL: MLL rearranged, HYPO: Hypodiploidy, iAMP21: intrachromosomal amplification of chromosome 21, HYPER: Hyperdiploidy. B) Comparison of the number of patients which gain, lose, or have the same number of mutations in epigenetic regulators and signaling factors at relapse. The McNemar test was used to calculate the P-values.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016990&req=5

Figure 4: Relapsed B-ALL is enriched for mutations in epigenetic regulatorsA) Gain or loss of somatic mutations in matched diagnosis-relapse samples from 30 pediatric B-ALL patients. Clonal mutations at relapse which were detected in a minor subclone at diagnosis and clonal mutations at diagnosis which became subclonal at relapse are shaded. MLL: MLL rearranged, HYPO: Hypodiploidy, iAMP21: intrachromosomal amplification of chromosome 21, HYPER: Hyperdiploidy. B) Comparison of the number of patients which gain, lose, or have the same number of mutations in epigenetic regulators and signaling factors at relapse. The McNemar test was used to calculate the P-values.
Mentions: Sequencing of the 30 matched relapsed samples showed a striking gain of mutations in epigenetic regulators, with 17 (57%) harboring a mutation. Of the 11 patients that gained a mutation in an epigenetic regulator at the time of relapse, only three were detectable in a rare subclone at diagnosis. (Fig 4A). As noted above, this frequency is comparable to other poor prognosis de novo ALL subgroups such as hypodiploid and ETP ALL. In addition to the 11 gains, five patients retained the same mutations from diagnosis, and one patient had their clonal mutation reduced to a subclonal allele frequency at relapse (Supplementary Fig. 1B). Details of each identified somatic mutation in each patient and a summary of mutations by molecular subtype are available in the supplemental materials (Supplementary Tables 3 and 4).

Bottom Line: Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples.Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort.We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.

ABSTRACT
Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signalling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.

Show MeSH
Related in: MedlinePlus