Evaluation of multiplex ligation dependent probe amplification (MLPA) for identification of acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21 (iAMP21) in a Brazilian population

This study aimed to evaluate in the Brazilian population, the genotypes and population frequencies of pharmacogenetic polymorphisms involved in the response to drugs used in treatment of acute lymphoblastic leukemia (ALL), and to compare the data with data from the HapMap populations. There was significant differentiation between most population pairs, but few associations between genetic ancestry and SNPs in the Brazilian population were observed. AMOVA analysis comparing the Brazilian population to all other populations retrieved from HapMap pointed to a genetic proximity with the European population. These associations point to preclusion of the use of genetic ancestry as a proxy for predicting drug response. In this way, any study aiming to correlate genotype with drug response in the Brazilian population should be based on pharmacogenetic SNP genotypes.

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Secondary Cytogenetic Abnormalities and Outcome in Children with TEL-AML1-Positive Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v106.11.1450.1450 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1450-1450

Author(s):

Oussama A. Abla ◽

Johann Hitzler ◽

Charles Ye ◽

Mohamed Abdelhaleem ◽

Ronald Grant ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Fusion Gene ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

Prognostic Indicator ◽

Similar Rate ◽

Chromosome 21 ◽

Prognostic Impact ◽

Extra Copy ◽

Cytogenetic Abnormalities

Abstract The t(12;21) translocation, which results in the fusion of the TEL (ETV6) and AML1 (RUNX1) genes, is present in ~25% of pediatric B-precusor acute lymphoblastic leukemia (ALL) patients. Although initially thought to be a favorable prognostic indicator, the t(12;21) was associated with a similar rate of relapse as t(12;21)-negative pre-B ALL in subsequent studies. While secondary cytogenetic abnormalities are often present, their prognostic significance is unknown. The objective of this study is therefore to examine the type, frequency and prognostic impact of secondary cytogenetic abnormalites in t(12;21)-positive blasts of children with ALL. We studied retrospectively 56 patients diagnosed with t(12;21)-positive ALL at the Hospital for Sick Children between 2000–2005. The mean age at diagnosis was 4.9 years (range <1 to 12 years). Nine patients (16%) presented with a white blood cell count of greater than 50 × 109/L. Cytogenetic studies consisted of a combination of FISH, G-banding and spectral karyotyping. The most frequent secondary cytogenetic changes in patients with t(12;21)-positive ALL were: the deletion of the non-translocated TEL allele (38%), an extra copy of the TEL-AML1 fusion gene (14%). Additional numerical abnormalities were seen in approximately one-third of the cases, with the most common being a gain of chromosome 21(13%). Recurrent deletions of chromosomal regions 6q and 11q were observed (14%). A surprising degree of karyotypic complexity was noted. Three or more additional chromosome abnormalities, two abnormal clonal lines, and complex structural rearrangements involving TEL-AML1 were detected in 28%, 21%, and 9% of patients, respectively. Five children (9%) in this cohort have developed a relapse of ALL. The 5-year event-free survival (EFS) was 83±7%. The 5-year EFS for patients with a deleted second TEL allele or an extra TEL-AML1 fusion was not statistically different. Of note, 4 of the children who relapsed had high-risk features at presentation (NCI criteria). All were treated with chemotherapy protocols developed for lower risk ALL. The realization that TEL-AML1 does not always predict excellent prognosis indicates that an on-going study of patients and their survival, with detailed analysis of complex genetic changes, is necessary for a reliable assessment of the prognostic value of the t(12;21) in pediatric ALL.

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Amplification of RUNX1 gene in two new cases of childhood B-cell precursor acute lymphoblastic leukemia: A case report

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e21000 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e21000-e21000

Author(s):

A. Fauzdar ◽

A. Mahajan ◽

D. Jain ◽

M. Mishra ◽

V. Raina

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Chromosome 21 ◽

Fish Analysis ◽

Cell Precursor ◽

Childhood All ◽

Mll Gene ◽

Runx1 Gene

e21000 Background: Chromosome abnormalities of leukemia cells have important prognostic significance in childhood acute lymphoblastic leukemia (ALL). B-cell precursor acute lymphoblastic leukemia (BCP-ALL) ETV6/RUNX1 (alias TEL/AML1) is most frequent i.e. 15 - 35% in the children with 2 - 18 age group. We report two new cases with Pre B- cell ALL without ETV6/RUNX1 rearrangement, showing amplification of AML1 gene detected by FISH analysis. Methods: Bone marrow samples were analyzed for chromosomal abnormalities with conventional G-banding techniques and interphase fluorescence in situ hybridization (FISH) using probes to detect BCR/ABL t(9;22)(q34-q11) fusion, cryptic TEL/AML1 t(12:21)(p13-q22) and MLL rearrangement for del 11q23. Results: In first case a 3-year girl with four copies of AML (RUNX1) gene were observed in 95% of the cell with normal two copies of TEL (ETV6) gene in both interphase and metaphase FISH. We observed BCR-ABL negative translocation and no MLL gene rearrangement in all the interphase cells after doing FISH. We got a normal 46XX karyotype from bone marrow with conventional cytogenetics (CC) in the same patient. In second case, a 4-year male we observed four copies of AML and two copies of TEL gene in more than 80% of cells. In this patient, we got BCR-ABL negative translocation and three copies of MLL gene without any rearrangement through FISH. We got normal 46XY karyotype in the same patient through CC. Conclusions: In both the patients, we observed hyperdiploidy detected with four copies of RUNX1 gene showing tetrasomy of chromosome 21 detected with metaphase FISH analysis whereas G-banding shows normal diploidy. Bone marrow karyotype in combination with molecular cytogenetic techniques like FISH should be done for improvement in sensitivity and accurate cytogenetic analysis in childhood ALL patients for proper identification of prognostic group for optimum treatment. This is one of the few reported studies worldwide for amplification of RUNX1 gene from Indian subcontinent in childhood BCP-ALL. No significant financial relationships to disclose.

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Association of CDKN2A/2B deletion with homozygous deletion of TCR- γ gene in T-ALL.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e18516 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e18516-e18516

Author(s):

Anita Chopra ◽

Jay Singh ◽

Deepak Verma ◽

Nishi Rajput ◽

Sameer Bakhshi ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Homozygous Deletion ◽

Quantitative Assay ◽

Predictors Of Outcome ◽

Genetic Aberrations ◽

The Status ◽

Probe Set ◽

Dependent Probe

e18516 Background: T-lineage acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that arises in a multistep fashion through acquisition of several genetic aberrations. Absence of biallelic deletion of TCR-γ (ABD), a marker of immaturity, and CDKN2A/2B deletion have been identified as poor predictors of outcome in T-ALL treated with contemporary protocols. The aim of this study was to determine the correlation between ABD and CDKN2A/2B in Indian T-ALL patients. Methods: A total of 31 cases of T-ALL, diagnosed on morphology, cytochemistry and immunophenotyping, were included in the study. The age of the patients ranged from 1-50 years. The patients were investigated for CDKN2A/2B deletion by multiplex ligation dependent probe amplification (MLPA) using the commercially available probe set P383 (MRC Holland). The status of the deletion of TCR- γ was determined using quantitative assay described by Gutierrez et al.1 Results: Absence of biallelic deletion of TCR- γ gene were found in 14 (45.16%) patients. Homozygous deletion was seen in 13 (41.93%) patients while monoallelic deletion was seen in 5 (16.12%) patients. CDKN2A/2B deletions were found in (48.38%) patients. On correlation of CDKN2A/2B deletion and TCR- γ deletion, it was found that CDKN2A/2B deletion was found in 2/14 (14.28%) patients with ABD and 10/13 (76.92%) patients with homozygous deletion. Conclusions: CDKN2A/2B deletion are more common in patients with homozygous deletion of TCR- γ gene.

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Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21)

Blood ◽

10.1182/blood-2006-08-040436 ◽

2006 ◽

Vol 109 (6) ◽

pp. 2327-2330 ◽

Cited By ~ 139

Author(s):

Anthony V. Moorman ◽

Susan M. Richards ◽

Hazel M. Robinson ◽

Jon C. Strefford ◽

Brenda E. S. Gibson ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Survival Data ◽

Lymphoblastic Leukemia ◽

White Cell Count ◽

Fold Increase ◽

Chromosome 21 ◽

Newly Diagnosed ◽

First Remission ◽

The Uk

Abstract Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 (84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.9 vs 12.4) compared with children without this abnormality. Notably, patients with iAMP21 had a significantly inferior event-free and overall survival at 5 years compared with other patients: 29% (95% confidence interval [CI], 13%-48%) versus 78% (95% CI, 76%-80%) and 71% (95% CI, 51%-84%) versus 87% (95% CI, 85%-88%), respectively. As a result of this 3-fold increase in relapse risk, newly diagnosed patients with iAMP21 recruited to the current UK MRC ALL2003 trial are being treated on the high-risk arm and are considered for bone marrow transplantation in first remission.

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Risk-Directed Treatment Intensification Significantly Reduces the Risk of Relapse Among Children and Adolescents With Acute Lymphoblastic Leukemia and Intrachromosomal Amplification of Chromosome 21: A Comparison of the MRC ALL97/99 and UKALL2003 Trials

Journal of Clinical Oncology ◽

10.1200/jco.2013.48.9377 ◽

2013 ◽

Vol 31 (27) ◽

pp. 3389-3396 ◽

Cited By ~ 76

Author(s):

Anthony V. Moorman ◽

Hazel Robinson ◽

Claire Schwab ◽

Sue M. Richards ◽

Jeremy Hancock ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Intensive Therapy ◽

Survival Rates ◽

Chromosome 21 ◽

Treatment Intensification ◽

Runx1 Gene ◽

Increased Risk ◽

First Remission ◽

Risk Of Relapse

Purpose To evaluate the effect on outcome of intensifying therapy for patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21). Patients and Methods We report two cohorts of patients treated on Medical Research Council ALL97 or United Kingdom (UK) ALL2003. iAMP21 was identified retrospectively in ALL97 and was not used to guide therapy. However, in UKALL2003, iAMP21 was determined prospectively, and patients were allocated to the most intensive treatment arm (regimen C), which included augmented Berlin-Frankfurt-Munster consolidation, escalating Capizzi maintenance, double delayed intensification, and an option for first remission transplantation. The presence of iAMP21 was determined by fluorescence in situ hybridization using probes specific for the RUNX1 gene. Results iAMP21 was identified in 2% of patients with B-cell precursor ALL treated on UKALL2003 and ALL97. The event-free survival, relapse, and overall survival rates at 5 years for iAMP21 patients treated on ALL97 and UKALL2003 were 29% and 78%, 70% and 16%, and 67% and 89%, respectively (all P < .01). Patients treated on ALL97 had an increased risk of relapse compared with patients treated on UKALL2003 (hazard ratio, 7.2; 95% CI, 2.91 to 17.87; P < .001). Conclusion iAMP21 patients with ALL benefitted from receiving more intensive therapy in UKALL2003. In UKALL2011, they will continue to be treated as cytogenetic high risk, receive intensive chemotherapy (regimen C), and will only be recommended for transplantation if they do not achieve a complete remission by the end of induction therapy. This study illustrates how the discovery and characterization of disease-specific genetic aberrations can be used to tailor therapy more precisely.

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Blood Spotlight on iAMP21 acute lymphoblastic leukemia (ALL), a high-risk pediatric disease

Blood ◽

10.1182/blood-2014-08-569228 ◽

2015 ◽

Vol 125 (9) ◽

pp. 1383-1386 ◽

Cited By ~ 53

Author(s):

Christine J. Harrison

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

White Cell Count ◽

Intensive Therapy ◽

Chromosome 21 ◽

Structural Rearrangements ◽

Cell Precursor ◽

High Relapse Rate ◽

Complex Structural ◽

Standard Risk

Abstract Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukemia. Breakage-fusion-bridge cycles followed by chromothripsis and other complex structural rearrangements of chromosome 21 underlie the mechanism giving rise to iAMP21. Patients with iAMP21 are older (median age 9 years), with a low white cell count. They have a high relapse rate when treated as standard risk. Recent studies have shown improved outcome on intensive therapy. Molecular targets for therapy are being sought.

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