title: Exome Sequencing in Classic Hairy Cell Leukaemia Reveals Widespread Variation in Acquired Somatic Mutations between Individual Tumours Apart from the Signature BRAF V(600)E Lesion.
abstract: In classic Hairy cell leukaemia (HCLc), a single case has thus far been interrogated by whole exome sequencing (WES) in a treatment naive patient, in which BRAF V(600)E was identified as an acquired somatic mutation and confirmed as occurring near-universally in this form of disease by conventional PCR-based cohort screens. It left open however the question whether other genome-wide mutations may also commonly occur at high frequency in presentation HCLc disease. To address this, we have carried out WES of 5 such typical HCLc cases, using highly purified splenic tumour cells paired with autologous T cells for germline. Apart from BRAF V(600)E, no other recurrent somatic mutation was identified in these HCLc exomes, thereby excluding additional acquired mutations as also prevalent at a near-universal frequency in this form of the disease. These data then place mutant BRAF at the centre of the neoplastic drive in HCLc. A comparison of our exome data with emerging genetic findings in HCL indicates that additional somatic mutations may however occur recurrently in smaller subsets of disease. As mutant BRAF alone is insufficient to drive malignant transformation in other histological cancers, it suggests that individual tumours utilise largely differing patterns of genetic somatic mutations to coalesce with BRAF V(600)E to drive pathogenesis of malignant HCLc disease.
authors.affiliation: Tumour Immunogenetics Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Weston-Bell
authors.affiliation: Genetic Epidemiology and Genomic Informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Will
authors.initials: W
authors.lastname: Tapper
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Studies, University of Southampton, Southampton, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Tumour Immunogenetics Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Dean
authors.initials: D
authors.lastname: Bryant
authors.affiliation: Tumour Immunogenetics Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Yurany
authors.initials: Y
authors.lastname: Moreno
authors.affiliation: Department of Preclinical Sciences, Faculty of Medical Sciences, University of The West Indies, St. Augustine, Trinidad and Tobago.
authors.forename: Melford
authors.initials: M
authors.lastname: John
authors.affiliation: Genetic Epidemiology and Genomic Informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Hanneke C
authors.initials: HC
authors.lastname: Kluin-Nelemans
authors.affiliation: Genetic Epidemiology and Genomic Informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Collins
authors.affiliation: Tumour Immunogenetics Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Surinder S
authors.initials: SS
authors.lastname: Sahota
mesh_terms: D004252:DNA Mutational Analysis; D059472:Exome; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013154:Spleen / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf