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Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus

Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus
Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus
Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically-acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2?Mb running from 14q32.12 to the telomere. Exome sequencing (n=7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P<0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r=0.76; P=0.0001). The absence of driver gene mutations in the exomes of 3 individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal hemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n=11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal hemopoiesis either as an initiating event or as a secondary change.
0887-6924
2069-2074
Chase, A.
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Leung, W.
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Tapper, W.
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Jones, A.V.
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Knoops, L.
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Rasi, C.
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Forsberg, L.A.
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Guglielmelli, P.
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Zoi, K.
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Hall, V.
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Chiecchio, L.
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Eder-Azanza, L.
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Bryant, C.
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Lannfelt, L.
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Docherty, L.
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White, H.E.
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Score, J
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Mackay, D.J.G.
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Vannucchi, A.M.
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Dumanski, J.P.
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Cross, N.C.P.
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Chase, A.
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Leung, W.
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Tapper, W.
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Jones, A.V.
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Knoops, L.
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Rasi, C.
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Forsberg, L.A.
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Guglielmelli, P.
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Zoi, K.
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Hall, V.
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Chiecchio, L.
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Eder-Azanza, L.
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Bryant, C.
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Lannfelt, L.
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Docherty, L.
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White, H.E.
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Score, J
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Mackay, D.J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Vannucchi, A.M.
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Dumanski, J.P.
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Cross, N.C.P.
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Chase, A., Leung, W., Tapper, W., Jones, A.V., Knoops, L., Rasi, C., Forsberg, L.A., Guglielmelli, P., Zoi, K., Hall, V., Chiecchio, L., Eder-Azanza, L., Bryant, C., Lannfelt, L., Docherty, L., White, H.E., Score, J, Mackay, D.J.G., Vannucchi, A.M., Dumanski, J.P. and Cross, N.C.P. (2015) Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus. Leukemia, 29 (10), 2069-2074. (doi:10.1038/leu.2015.130). (PMID:26114957)

Record type: Article

Abstract

Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically-acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2?Mb running from 14q32.12 to the telomere. Exome sequencing (n=7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P<0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r=0.76; P=0.0001). The absence of driver gene mutations in the exomes of 3 individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal hemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n=11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal hemopoiesis either as an initiating event or as a secondary change.

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Accepted/In Press date: 1 May 2015
e-pub ahead of print date: 31 July 2015
Published date: October 2015
Organisations: Human Development & Health

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Local EPrints ID: 378524
URI: https://eprints.soton.ac.uk/id/eprint/378524
ISSN: 0887-6924
PURE UUID: e85b770a-d680-48bf-b2bb-9a388e0ecdf3
ORCID for D.J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401
ORCID for N.C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 06 Jul 2015 11:08
Last modified: 06 Jun 2018 12:54

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Contributors

Author: A. Chase
Author: W. Leung
Author: W. Tapper
Author: A.V. Jones
Author: L. Knoops
Author: C. Rasi
Author: L.A. Forsberg
Author: P. Guglielmelli
Author: K. Zoi
Author: V. Hall
Author: L. Chiecchio
Author: L. Eder-Azanza
Author: C. Bryant
Author: L. Lannfelt
Author: L. Docherty
Author: H.E. White
Author: J Score
Author: D.J.G. Mackay ORCID iD
Author: A.M. Vannucchi
Author: J.P. Dumanski
Author: N.C.P. Cross ORCID iD

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