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 three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. 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 haemopoiesis either as an initiating event or as a secondary change.
Highlights
Uniparental disomy (UPD) refers to the situation in which both copies of a chromosome pair or parts of chromosomes have originated from one parent
Several other regions of recurrent acquired UPD (aUPD) have been identified for which the target is unknown, for example, chromosome 14q aUPD is seen in myeloid neoplasms[2] and is one of the most common abnormalities associated with clonal haemopoiesis in population cohorts of elderly individuals.[3,4]
We analysed in house array data on cases with myeloproliferative neoplasm (MPN) or MDS/MPN and identified aUPD14q extending to the 14q telomere in 25 cases
Summary
Uniparental disomy (UPD) refers to the situation in which both copies of a chromosome pair or parts of chromosomes have originated from one parent. Regions of aUPD were defined as a region of allelic imbalance (segmented mirrored BAF 40.56) with neutral copy number (log R ratio ~ 0) that extended to the telomere.[12] For samples with known JAK2 V617F levels, determined by pyrosequencing,[13] and BAF for both aUPD9p and aUPD14q aUPD, we were able to calculate both the proportion of cells with aUPD14 and the proportion of cells which were homozygous or heterozygous for JAK2 V617F This allowed us to infer the likely order of acquisition of aUPD14 and JAK2 V617F (see Supplementary Table 2 for detailed calculations). The minimally affected region identified in patient E5364 (chr14:94,245,652-qter) was interrogated in all aUPD14q exomes for rare variants that were either novel or had a minor allele frequency of ⩽ 1% in databases of common variation (1000 genomes, Complete Genomics, Exome Variant Server)
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