title: Rapid Molecular Profiling of Myeloproliferative Neoplasms Using Targeted Exon Resequencing of 86 Genes Involved in JAK-STAT Signaling and Epigenetic Regulation.
abstract: Myeloproliferative neoplasms (MPNs) are a heterogeneous group of blood disorders characterized by excess production of mature blood cells and an increased risk of late transformation to acute myeloid leukemia or primary myelofibrosis. Approximately 15% of MPN cases do not carry mutations in JAK2, CALR, or MPL and are thus often referred to as triple-negative cases. These are caused by a diverse set of rare mutations in cytokine receptors, JAK-STAT signaling pathway components, or epigenetic modifiers. In addition, some cases diagnosed as MPN are reactive rather than clonal disorders, so a negative result from a genetic screen can be informative. To obtain a comprehensive rapid molecular diagnosis for most MPNs, we developed an assay to detect genetic mutations (single nucleotide variants and/or small insertions/deletions) in 86 genes using targeted exon resequencing (AmpliSeq) and a bench-top semiconductor machine (Ion Torrent Personal Genome Machine). Our assay reliably detects well characterized mutations in JAK2, CALR, and MPL, but also rarer mutations in ASXL1, TET2, SH2B3, and other genes. Some of these mutations are novel. We find multiple mutations in advanced cases, suggesting co-operation between Janus kinase-STAT pathway mutations and epigenetic mutations in disease progression. This assay can be used to follow molecular progression, clonal heterogeneity, and drug resistance in MPNs.
authors.affiliation: Mater Research Institute, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Graham W
authors.initials: GW
authors.lastname: Magor
authors.affiliation: Mater Research Institute, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Tallack
authors.affiliation: School of Medicine, Faculty of Medicine and Biomedical Sciences, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Klose
authors.affiliation: Department of Pathology, Mater Health Services, Mater Hospital, South Brisbane, Queensland, Australia.
authors.forename: Debra
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, Queensland, Australia; Centre for Personalized Nanomedicine, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Darren
authors.initials: D
authors.lastname: Korbie
authors.affiliation: School of Medicine, Faculty of Medicine and Biomedical Sciences, The University of Queensland, St. Lucia, Queensland, Australia; Department of Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Mollee
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, Queensland, Australia; Centre for Personalized Nanomedicine, The University of Queensland, St. Lucia, Queensland, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Matt
authors.initials: M
authors.lastname: Trau
authors.affiliation: Mater Research Institute, The University of Queensland, St. Lucia, Queensland, Australia; Department of Pathology, Mater Health Services, Mater Hospital, South Brisbane, Queensland, Australia; Department of Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia; ICON Cancer Care, Milton, Queensland, Australia. Electronic address: andrew.perkins@mater.uq.edu.au.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Perkins
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015415:Biomarkers; D019295:Computational Biology / Q000379:methods; D044127:Epigenesis, Genetic; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D050791:STAT Transcription Factors / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D050791:STAT Transcription Factors; D053612:Janus Kinases