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

• Published in: Blood Vol. 115; no. 17; pp. 3553 - 3558
• Main Authors: Bateman, Caroline M., Colman, Susan M., Chaplin, Tracy, Young, Bryan D., Eden, Tim O., Bhakta, Manoo, Gratias, Eric J., van Wering, Elisabeth R., Cazzaniga, Giovanni, Harrison, Christine J., Hain, Richard, Ancliff, Philip, Ford, Anthony M., Kearney, Lyndal, Greaves, Mel
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 29.04.2010; Americain Society of Hematology
• Subjects: Biological and medical sciences; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; Female; Gene Dosage; Genome-Wide Association Study; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Mutation; Oligonucleotide Array Sequence Analysis; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Twins, Monozygotic; Hematology; Copy number; Lymphoproliferative syndrome; Malignant hemopathy; Acute lymphocytic leukemia; Genome; Monozygotic twin; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-10-251413

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 (∼ 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.