title: Evolutionary trajectories of hyperdiploid ALL in monozygotic twins.
abstract: Identical twins have provided unique insights on timing or sequence of genetic events in acute lymphoblastic leukaemia (ALL). To date, this has mainly focused on ALL with MLL or ETV6-RUNX1 fusions, with hyperdiploid ALL remaining less well characterised. We examined three pairs of monozygotic twins, two concordant and one discordant for hyperdiploid ALL, for single-nucleotide polymorphism (SNP)-defined copy number alterations (CNAs), IGH/L plus TCR gene rearrangements and mutations in NRAS, KRAS, FLT3 and PTPN11 genes. We performed whole exome sequencing in one concordant twin pair. Potential 'driver' CNAs were low, 0-3 per case, and all were different within a pair. One patient had an NRAS mutation that was lacking from leukaemic cells of the twin sibling. By exome sequencing, there were 12 nonsynonymous mutations found in one twin and 5 in the other, one of which in SCL44A2 was shared or identical. Concordant pairs had some identical IGH/L and TCR rearrangements. In the twin pair with discordant hyperdiploid ALL, the healthy co-twin had persistent low level hyperdiploid CD19+ cells that lacked a CNA present in the ALL cells of her sibling. From these data, we propose that hyperdiploid ALL arises in a pre-B cell in utero and mutational changes necessary for clinical ALL accumulate subclonally and postnatally.
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Bateman
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, UK.
authors.forename: D
authors.initials: D
authors.lastname: Alpar
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Ford
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Colman
authors.affiliation: Molecular Diagnostics, Division of Molecular Pathology, The Institute of Cancer Research, Sutton, UK.
authors.forename: D
authors.initials: D
authors.lastname: Wren
authors.affiliation: Department of Haematology, University Hospital Southampton, Southampton, UK.
authors.forename: M
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, UK.
authors.forename: L
authors.initials: L
authors.lastname: Kearney
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, UK.
authors.forename: M
authors.initials: M
authors.lastname: Greaves
mesh_terms: D017931:DNA Primers; D004171:Diploidy; D019143:Evolution, Molecular; D059472:Exome; D015329:Gene Rearrangement, T-Lymphocyte; D005803:Genes, Immunoglobulin; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014430:Twins, Monozygotic
chemical_list: D017931:DNA Primers