COMPREHENSIVE MOLECULAR CYTOGENETIC ANALYSES OF BONE MARROW CELLS IN 64 CHILDREN WITH T-ALL REVEALED PROGNOSTICALLY RELEVANT RECURRENT FINDINGS
(Abstract release date: 05/18/17)
EHA Library. Lizcova L. 05/18/17; 182334; PB1620
Dr. Libuse Lizcova
Contributions
Contributions
Abstract
Abstract: PB1620
Type: Publication Only
Background
T-ALL represents 15% of newly diagnosed children with ALL and it is a clinically and genetically heterogeneous disease. Despite the use of intensive chemotherapy, relapse occurs in almost 25% of patients whose outcome remains dismal. Visible chromosomal aberrations are seen in approximately half of the cases, while cytogenetically cryptic aberrations are observed in almost all cases of T-ALL. However, prognostic implication of majority of them still remains unclear.
Aims
The aim of this study was to retrospectively and prospectively analyze bone marrow cells of children with T-ALL, to determine a frequency of recurrent cryptic chromosomal aberrations and to assess their impact on event free (EFS) and overall survival (OS).
Methods
Bone marrow cells of all patients were analyzed at the time of diagnosis by combination of conventional and molecular cytogenetic methods. For detection of the most frequent known chromosomal changes, i.e. rearrangements of TCR loci (TRA-14q11, TRB-7q34, TRG-7p14) and TLX3 gene (5q35), deletion of CDKN2A (9p21) and amplification of ABL1 (9q34), interphase FISH with locus-specific probes (Dako, Abbott Molecular) was used. Complex chromosomal rearrangements were proved by multicolor FISH and multicolor banding (24XCyte/XCyte Probe Kit; MetaSystems) or CGH-SNP array (SurePrint G3 Cancer CGH+SNP 4x180K, Agilent). For OS and EFS Kaplan-Maier analysis with Mantel Cox test was done.
Results
During the years 1996-2016 we examined archived material of 64 children with T-ALL (19 girls and 45 boys, median age 8.25 years). In total, chromosomal aberrations were detected in 86% of patients. The most frequent aberration was deletion of CDKN2A gene, which was found in 35/64 patients (19x homozygous, 16x heterozygous). Rearrangements of TCR loci were detected in 17/64 children (11x TRA, 6x TRB). TLX3 gene rearrangement was established in 15/64 patients. No aberration of TRG gene and amplification of ABL1 were found. Complex chromosomal aberrations were proved in 12/64 children. In two cases, isochromosome of the long arm of chromosome 9 was found. 48 patients are living in the first/second complete remission. Relapse of the disease occurred in 17 patients, 16 children died. Best outcome (EFS and OS) was associated with TRA translocations (p<0.05). Patients with TLX3 rearrangement had significantly shorter OS and EFS (p<0.05).
Conclusion
Using molecular cytogenetic methods cryptic recurrent aberrations were proved in vast majority of patients. Rearrangement of TLX3 gene was related to poor outcome in contrast to TRA translocations associated with more favorable course of the disease. Our work attempts to clear up the significance of chromosomal aberrations related to childhood T-ALL in order to facilitate the patients´ stratification into cytogenetic prognostic groups and to identify patients at an increased risk of relapse similarly like it has been adopted in pB-ALL.
Supported by grants RVO-VFN64165, GACR-P302/12/G157 and NPU I nr.LO1604
Session topic: 1. Acute lymphoblastic leukemia - Biology
Keyword(s): T-ALL, Prognostic factor, Molecular cytogenetics, Children
Abstract: PB1620
Type: Publication Only
Background
T-ALL represents 15% of newly diagnosed children with ALL and it is a clinically and genetically heterogeneous disease. Despite the use of intensive chemotherapy, relapse occurs in almost 25% of patients whose outcome remains dismal. Visible chromosomal aberrations are seen in approximately half of the cases, while cytogenetically cryptic aberrations are observed in almost all cases of T-ALL. However, prognostic implication of majority of them still remains unclear.
Aims
The aim of this study was to retrospectively and prospectively analyze bone marrow cells of children with T-ALL, to determine a frequency of recurrent cryptic chromosomal aberrations and to assess their impact on event free (EFS) and overall survival (OS).
Methods
Bone marrow cells of all patients were analyzed at the time of diagnosis by combination of conventional and molecular cytogenetic methods. For detection of the most frequent known chromosomal changes, i.e. rearrangements of TCR loci (TRA-14q11, TRB-7q34, TRG-7p14) and TLX3 gene (5q35), deletion of CDKN2A (9p21) and amplification of ABL1 (9q34), interphase FISH with locus-specific probes (Dako, Abbott Molecular) was used. Complex chromosomal rearrangements were proved by multicolor FISH and multicolor banding (24XCyte/XCyte Probe Kit; MetaSystems) or CGH-SNP array (SurePrint G3 Cancer CGH+SNP 4x180K, Agilent). For OS and EFS Kaplan-Maier analysis with Mantel Cox test was done.
Results
During the years 1996-2016 we examined archived material of 64 children with T-ALL (19 girls and 45 boys, median age 8.25 years). In total, chromosomal aberrations were detected in 86% of patients. The most frequent aberration was deletion of CDKN2A gene, which was found in 35/64 patients (19x homozygous, 16x heterozygous). Rearrangements of TCR loci were detected in 17/64 children (11x TRA, 6x TRB). TLX3 gene rearrangement was established in 15/64 patients. No aberration of TRG gene and amplification of ABL1 were found. Complex chromosomal aberrations were proved in 12/64 children. In two cases, isochromosome of the long arm of chromosome 9 was found. 48 patients are living in the first/second complete remission. Relapse of the disease occurred in 17 patients, 16 children died. Best outcome (EFS and OS) was associated with TRA translocations (p<0.05). Patients with TLX3 rearrangement had significantly shorter OS and EFS (p<0.05).
Conclusion
Using molecular cytogenetic methods cryptic recurrent aberrations were proved in vast majority of patients. Rearrangement of TLX3 gene was related to poor outcome in contrast to TRA translocations associated with more favorable course of the disease. Our work attempts to clear up the significance of chromosomal aberrations related to childhood T-ALL in order to facilitate the patients´ stratification into cytogenetic prognostic groups and to identify patients at an increased risk of relapse similarly like it has been adopted in pB-ALL.
Supported by grants RVO-VFN64165, GACR-P302/12/G157 and NPU I nr.LO1604
Session topic: 1. Acute lymphoblastic leukemia - Biology
Keyword(s): T-ALL, Prognostic factor, Molecular cytogenetics, Children
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