Genome-wide DNA copy number analysis of acute lymphoblastic leukemia identifies new genetic markers associated with clinical outcome

Abstract

Identifying additional genetic alterations associated with poor prognosis in acute lymphoblastic leukemia (ALL) is still a challenge. Aims: To characterize the presence of additional DNA copy number alterations (CNAs) in children and adults with ALL by whole-genome oligonucleotide array (aCGH) analysis, and to identify their associations with clinical features and outcome. Array-CGH was carried out in 265 newly diagnosed ALLs (142 children and 123 adults). The NimbleGen CGH 12x135K array (Roche) was used to analyze genetic gains and losses. CNAs were analyzed with GISTIC and aCGHweb software. Clinical and biological variables were analyzed. Three of the patients showed chromothripsis (cth6, cth14q and cth15q). CNAs were associated with age, phenotype, genetic subtype and overall survival (OS). In the whole cohort of children, the losses on 14q32.33 (p = 0.019) and 15q13.2 (p = 0.04) were related to shorter OS. In the group of children without good- or poor-risk cytogenetics, the gain on 1p36.11 was a prognostic marker independently associated with shorter OS. In adults, the gains on 19q13.2 (p = 0.001) and Xp21.1 (p = 0.029), and the loss of 17p (p = 0.014) were independent markers of poor prognosis with respect to OS. In summary, CNAs are frequent in ALL and are associated with clinical parameters and survival. Genome-wide DNA copy number analysis allows the identification of genetic markers that predict clinical outcome, suggesting that detection of these genetic lesions will be useful in the management of patients newly diagnosed with ALL. ; The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n°306242-NGS-PTL, the Fundación Castellano Leonesa de Hematología y Hemoterapia (FUCALHH 2013), the Consejería de Educación, Junta de Castilla y León (HUS272U13), Proyectos de Investigación del SACYL, Spain: GRS 994/A/14, BIO/SA10/14, BIO/SA31/13. The work was partially supported by grants from the Spanish Fondo de Investigaciones Sanitarias FIS 09/01543, PI12/00281, COST Action EuGESMA (BM0801), Fundación Española de Hematología y Hemoterapia (FEHH), and by grants (RD12/0036/0069) from the Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (ERDF) "Una manera de hacer Europa" (Innocampus; CEI-2010-1-0010). MFC was supported by study commission (no. 223-2011) granted by the Universidad Pedagógica y Tecnológica de Colombia, Colombia. ; Peer Reviewed