Genome-Wide DNA Copy Number Analysis of Acute Lymphoblastic Leukemia Identifies New Genetic Markers Associated with Clinical Outcome.

Maribel Forero-Castro,Jordi Ribera,Cristina Robledo,Marta Megido,Magdalena Sierra,Jesús M Hernández-Rivas,Juana Ciudad Pizarro,María Abáigar,Natalia De Las Heras,Maryam Arefi,Jonathan Quintero,Jorge Labrador,José M Alonso,Isabel Recio,Lourdes Hermosín,Susana Riesco,Ignacio De La Fuente,C Olivier ,Luis A Corchete ,José Luís Fuster ,Rocí­o Benito ,Juan Nicolás Rodríguez ,José María Ribera ,Juan Luis Garcı́a ,Ana A Martín

doi:10.1371/journal.pone.0148972

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.

Highlights

Acute lymphoblastic leukemia (ALL) is a malignancy of lymphoid progenitor cells characterized by marked heterogeneity at the molecular and clinical levels [1,2,3]
One of the current challenges in the study of ALL is to identify hidden genomic lesions that may be related to patient outcome [3, 6]
High-density resolution array-based comparative genomic hybridization (aCGH) has been used in hematological malignancies to identify submicroscopic copy number gains and losses across the genome [26]

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is a malignancy of lymphoid progenitor cells characterized by marked heterogeneity at the molecular and clinical levels [1,2,3]. The WHO classification divides ALL with respect to the presence of genetic abnormalities and it is well known that many of them are strong independent predictive factors of outcome [4]. Most adult patients are considered to be high-risk with a disease-free survival rate of

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Conclusion