title: Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia.
abstract: Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre- and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation.
authors.affiliation: Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Yussanne
authors.initials: Y
authors.lastname: Ma
authors.forename: Sara E
authors.initials: SE
authors.lastname: Dobbins
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sherborne
authors.forename: Daniel
authors.initials: D
authors.lastname: Chubb
authors.forename: Marta
authors.initials: M
authors.lastname: Galbiati
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Concetta
authors.initials: C
authors.lastname: Micalizzi
authors.forename: Rick
authors.initials: R
authors.lastname: Tearle
authors.forename: Amy L
authors.initials: AL
authors.lastname: Lloyd
authors.forename: Richard
authors.initials: R
authors.lastname: Hain
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D013997:Time Factors