Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia

Yussanne Ma, Sara E. Dobbins, Amy L. Sherborne, Daniel Chubb, Marta Galbiati, Giovanni Cazzaniga, Concetta Micalizzi, Rick Tearle, Amy L. Lloyd, Richard Hain, Mel Greaves, Richard S. Houlston

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)7429-7433
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number18
DOIs
Publication statusPublished - Apr 30 2013

Keywords

  • Copy number variants
  • Fusion gene

ASJC Scopus subject areas

  • General

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