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

• Published in: PloS one Vol. 11; no. 2; p. e0148972
• Main Authors: Forero-Castro, Maribel, Robledo, Cristina, Benito, Rocío, Abáigar, María, África Martín, Ana, Arefi, Maryam, Fuster, José Luis, de las Heras, Natalia, Rodríguez, Juan N., Quintero, Jonathan, Riesco, Susana, Hermosín, Lourdes, de la Fuente, Ignacio, Recio, Isabel, Ribera, Jordi, Labrador, Jorge, Alonso, José M., Olivier, Carmen, Sierra, Magdalena, Megido, Marta, Corchete-Sánchez, Luis A., Ciudad Pizarro, Juana, García, Juan Luis, Ribera, José M., Hernández-Rivas, Jesús M.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.02.2016; Public Library of Science (PLoS)
• Subjects: Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Adolescent; Adult; Adults; Aged; Aged, 80 and over; Apoptosis; Biology and Life Sciences; Biomarkers, Tumor - genetics; Blood; Bone marrow; Cancer; Cell cycle; Child; Child, Preschool; Children; Classification; Comparative Genomic Hybridization; Copy number; Cytogenetics; Deoxyribonucleic acid; DNA; DNA Copy Number Variations; DNA microarrays; Female; Gene Dosage; Gene Frequency; Genetic aspects; Genetic Markers; Genetic Predisposition to Disease; Genetic variation; Genome-Wide Association Study; Genomes; Hematology; Humans; Infant; Infant, Newborn; Kaplan-Meier Estimate; Lesions; Leukemia; Lymphatic leukemia; Male; Markers; Medical prognosis; Medical research; Medicine and Health Sciences; Middle Aged; Multivariate Analysis; Oligonucleotides; Parameter identification; Patient outcomes; Patients; Pediatrics; People and Places; Physiological aspects; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Prognosis; Proportional Hazards Models; Studies; Survival; Treatment Outcome; Young Adult; Colombia; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0148972

Identifying additional genetic alterations associated with poor prognosis in acute lymphoblastic leukemia (ALL) is still a challenge. 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.