title: Identification of a HMGA2-EFCAB6 gene rearrangement following next-generation sequencing in a patient with a t(12;22)(q14.3;q13.2) and JAK2V617F-positive myeloproliferative neoplasm.
abstract: Myeloproliferative neoplasms (MPNs) result from genetically altered hematopoietic stem cells that retain the capacity for multilineage differentiation. The study of genomic mutations identified so far suggests that they occur after a common ancestral event or that different mutations result in similar MPN phenotypes. We report analysis of a chromosomal translocation, t(12;22)(q14.3;q13.2), in a patient with a BCR-ABL1-negative, JAK2V617F-positive MPN. Comparative genomic hybridization (CGH) array and targeted sequencing detected no mutation in nine genes reported to influence the JAK2V617F-driven MPNs (MPL, LNK, CBL, TET2, EZH2, IKZF1, IDH1, IDH2, ASXL1). Next-generation sequencing revealed a balanced HMGA2-EFCAB6 genomic rearrangement. The HMGA2 breakpoint leads to the loss of seven 3'UTR binding sites for the microRNA (miRNA) let-7 tumor suppressor. The breakpoint in the EFCAB6 gene abrogates transcription of EFCAB6. Measurement of expression showed retention of HMGA2 transcription and no detectable EFCAB6 transcript. Allele burden comparison in a sample containing the translocation, showed 90% HMGA2-EFCAB6 versus 50% JAK2V617F allele dose, suggesting HMGA2-EFCAB6 rearrangement plays a more ancestral role, pre-JAK2V617F, in the neoplastic process. The pathogenicity of the translocation may rest on collaborations among JAK2V617F-induced constitutive activation of JAK2, the oncogenic property of HMGA2, and disrupted pathways, such as alteration in DJ-1 expression, resulting from the impact of EFCAB6 abrogation.
authors: Helen F. Graham Cancer Center, Newark, DE, USA. semartin@cbg.org
authors: S Eric
authors: SE
authors: Martin
authors: Mark
authors: M
authors: Sausen
authors: Abraham
authors: A
authors: Joseph
authors: Brewster F
authors: BF
authors: Kingham
authors: Eric S
authors: ES
authors: Martin
mesh_terms: D000368:Aged; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D015321:Gene Rearrangement; D025743:HMGA2 Protein / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D000071617:Protein Deglycase DJ-1; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic
chemical_list: D025743:HMGA2 Protein; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1