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

• Main Authors: Chase, A. (Author), Leung, W. (Author), Tapper, W. (Author), Jones, A.V (Author), Knoops, L. (Author), Rasi, C. (Author), Forsberg, L.A (Author), Guglielmelli, P. (Author), Zoi, K. (Author), Hall, V. (Author), Chiecchio, L. (Author), Eder-Azanza, L. (Author), Bryant, C. (Author), Lannfelt, L. (Author), Docherty, L. (Author), White, H.E (Author), Score, J (Author), Mackay, D.J.G (Author), Vannucchi, A.M (Author), Dumanski, J.P (Author), Cross, N.C.P (Author)
• Format: Article
• Language: English
• Published: 2015-10.
• Subjects: Article
• Online Access: Get fulltext

 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.