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)
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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