Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia.
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 ( 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.
Bateman
Caroline M
CM
Section of Haemato-Oncology, The Institute of Cancer Research, Surrey, UK.
Colman
Susan M
SM
Chaplin
Tracy
T
Young
Bryan D
BD
Eden
Tim O
TO
Bhakta
Manoo
M
Gratias
Eric J
EJ
van Wering
Elisabeth R
ER
Cazzaniga
Giovanni
G
Harrison
Christine J
CJ
Hain
Richard
R
Ancliff
Philip
P
Ford
Anthony M
AM
Kearney
Lyndal
L
Greaves
Mel
M
D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D014430:Twins, Monozygotic; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein