title: Biallelic loss of CDKN2A is associated with poor response to treatment in pediatric acute lymphoblastic leukemia.
abstract: The inactivation of tumor suppressor genes located within 9p21 locus (CDKN2A, CDKN2B) occurs in up to 30% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but its independent prognostic significance remains controversial. In order to investigate the prognostic impact of deletions and promoter methylation within 9p21, 641 children with newly diagnosed BCP-ALL using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) were investigated. A total of 169 (26.4%) microdeletions in 9p21 were detected, of which 71 were homozygous. Patients with CDKN2A homozygous deletions were older at diagnosis (p < .001), more frequently steroid resistant (p = .049), had higher WBC count (p < .001), higher MRD at Day 15 (p = .013) and lower relapse-free survival [p = .028, hazard ratio: 2.28 (95% confidence interval: 1.09-4.76)] than patients without these alterations. CDKN2A homozygous deletions coexisted with IKZF1 and PAX5 deletions (p < .001). In conclusion, CDKN2A homozygous deletions, but not promoter methylation, are associated with poor response to treatment and increased relapse risk of pediatric BCP-ALL.
authors.affiliation: a Department of Pediatrics, Oncology, Hematology and Diabetology , Medical University of Lodz , Lodz , Poland.|b Department of Pathology , Medical University of Lodz , Lodz , Poland.|c Postgraduate School of Molecular Medicine , Medical University of Warsaw , Warsaw , Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Braun
authors.affiliation: a Department of Pediatrics, Oncology, Hematology and Diabetology , Medical University of Lodz , Lodz , Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Pastorczak
authors.affiliation: d Department of Biostatistics and Translational Medicine , Medical University of Lodz , Lodz , Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Fendler
authors.affiliation: a Department of Pediatrics, Oncology, Hematology and Diabetology , Medical University of Lodz , Lodz , Poland.|c Postgraduate School of Molecular Medicine , Medical University of Warsaw , Warsaw , Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Madzio
authors.affiliation: d Department of Biostatistics and Translational Medicine , Medical University of Lodz , Lodz , Poland.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Tomasik
authors.affiliation: a Department of Pediatrics, Oncology, Hematology and Diabetology , Medical University of Lodz , Lodz , Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Taha
authors.affiliation: a Department of Pediatrics, Oncology, Hematology and Diabetology , Medical University of Lodz , Lodz , Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Bielska
authors.affiliation: e Department of Pediatric Hematology and Oncology , Medical University of Silesia , Zabrze , Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Sedek
authors.affiliation: e Department of Pediatric Hematology and Oncology , Medical University of Silesia , Zabrze , Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Szczepanski
authors.affiliation: f Department of Pediatric Hematology and Oncology , Medical University of Warsaw , Warsaw , Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Matysiak
authors.affiliation: g Department of Pediatric Hematology , Oncology and Transplantology, University of Medical Sciences , Poznan , Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Derwich
authors.affiliation: h Department of Pediatric Hematology and Oncology , Medical University of Lublin , Lublin , Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Lejman
authors.affiliation: h Department of Pediatric Hematology and Oncology , Medical University of Lublin , Lublin , Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kowalczyk
authors.affiliation: i Department of Pediatric Hematology , Oncology and Transplantology, Medical University of Wroclaw , Wroclaw , Poland.
authors.forename: Bernarda
authors.initials: B
authors.lastname: Kazanowska
authors.affiliation: j Department of Pediatric Hematology and Oncology , Olsztyn , Poland.
authors.forename: Wanda
authors.initials: W
authors.lastname: Badowska
authors.affiliation: k Department of Pediatric Hematology and Oncology, Collegium Medicum , Nicolaus Copernicus University , Bydgoszcz , Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Styczynski
authors.affiliation: l Department of Pediatric Hematology , Gdansk Medical University , Gdansk , Poland.
authors.forename: Nina
authors.initials: N
authors.lastname: Irga-Jaworska
authors.affiliation: a Department of Pediatrics, Oncology, Hematology and Diabetology , Medical University of Lodz , Lodz , Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Trelinska
authors.affiliation: a Department of Pediatrics, Oncology, Hematology and Diabetology , Medical University of Lodz , Lodz , Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Zalewska-Szewczyk
authors.affiliation: a Department of Pediatrics, Oncology, Hematology and Diabetology , Medical University of Lodz , Lodz , Poland.
authors.forename: Filip
authors.initials: F
authors.lastname: Pierlejewski
authors.affiliation: m Center for Human Genetics, KU Leuven , Leuven , Belgium.
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
authors.affiliation: a Department of Pediatrics, Oncology, Hematology and Diabetology , Medical University of Lodz , Lodz , Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Młynarski
mesh_terms: D014408:Biomarkers, Tumor; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D019942:Genes, p16; D006720:Homozygote; D006801:Humans; D008297:Male; D018365:Neoplasm, Residual / Q000235:genetics; D011003:Ploidies; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models
chemical_list: D014408:Biomarkers, Tumor
keywords: 9p21 chromosomal region; Childhood BCP-ALL; MLPA; MRD; microdeletions; prognostic factors