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dc.contributor.authorBateman, Caroline M
dc.contributor.authorColman, Susan M
dc.contributor.authorChaplin, Tracy
dc.contributor.authorYoung, Bryan D
dc.contributor.authorEden, Tim O B
dc.contributor.authorBhakta, Manoo
dc.contributor.authorGratias, Eric J
dc.contributor.authorvan Wering, Elisabeth R
dc.contributor.authorCazzaniga, Giovanni
dc.contributor.authorHarrison, Christine J
dc.contributor.authorHain, Richard
dc.contributor.authorAncliff, Philip
dc.contributor.authorFord, Anthony M
dc.contributor.authorKearney, Lyndal
dc.contributor.authorGreaves, Mel F
dc.date.accessioned2010-08-11T11:01:38Z
dc.date.available2010-08-11T11:01:38Z
dc.date.issued2010-04-29
dc.identifier.citationAcquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. 2010, 115 (17):3553-8 Blooden
dc.identifier.issn1528-0020
dc.identifier.pmid20061556
dc.identifier.doi10.1182/blood-2009-10-251413
dc.identifier.urihttp://hdl.handle.net/10541/109480
dc.description.abstractChimeric 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 ( approximately 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.
dc.language.isoenen
dc.subjectPrecursor Cell Lymphoblastic Leukaemia-Lymphomaen
dc.subject.meshCore Binding Factor Alpha 2 Subunit
dc.subject.meshFemale
dc.subject.meshGene Dosage
dc.subject.meshGenome-Wide Association Study
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshMutation
dc.subject.meshOligonucleotide Array Sequence Analysis
dc.subject.meshOncogene Proteins, Fusion
dc.subject.meshPolymorphism, Single Nucleotide
dc.subject.meshPrecursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.meshTwins, Monozygotic
dc.titleAcquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia.en
dc.typeArticleen
dc.contributor.departmentSection of Haemato-Oncology, The Institute of Cancer Research, Surrey, UK.en
dc.identifier.journalBlooden
html.description.abstractChimeric 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 ( approximately 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.


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