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Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia

Lookup NU author(s): Professor Christine Harrison FRCPath FMedSci


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Chimeric fusion genes are highly prevalent in childhood acute lymphoblastic leukemia (ALL) and are mostly prenatal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple (similar to 6 per case) copy number alterations (CNAs) as revealed by genome-wide single-nucleotide polymorphism arrays. Recurrent CNAs are probably "driver" events contributing critically to clonal diversification and selection, but at diagnosis, their developmental timing is "buried" in the leukemia's covert natural history. This conundrum can be resolved with twin pairs. We identified and compared CNAs in 5 pairs of monozygotic twins with concordant ETV6-RUNX1-positive ALL and 1 pair discordant for ETV6-RUNX1 positive ALL. We compared, within each pair, CNAs classified as potential "driver" or "passenger" mutations based upon recurrency and, where known, gene function. An average of 5.1 (range 3-11) CNAs (excluding immunoglobulin/T-cell receptor alterations) were identified per case. All "driver" CNAs (total of 32) were distinct within each of the 5 twin pairs with concordant ALL. "Driver" CNAs in another twin with ALL were all absent in the shared ETV6-RUNX1-positive preleukemic clone of her healthy co-twin. These data place all "driver" CNAs secondary to the prenatal gene fusion event and most probably postnatal in the sequential, molecular pathogenesis of ALL. (Blood. 2010; 115(17): 3553-3558)

Publication metadata

Author(s): Bateman CM, Colman SM, Chaplin T, Young BD, Eden TO, Bhakta M, Gratias EJ, van Wering ER, Cazzaniga G, Harrison CJ, Hain R, Ancliff P, Ford AM, Kearney L, Greaves M

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2010

Volume: 115

Issue: 17

Pages: 3553-3558

Print publication date: 29/04/2010

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology


DOI: 10.1182/blood-2009-10-251413


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