Chromosomal microarray analysis is superior in identifying cryptic aberrations in patients with acute lymphoblastic leukemia at diagnosis/relapse as a single assay

Abstract

Introduction Conventional cytogenetics (CC) is important in diagnosis, therapy, monitoring of post‐transplant bone marrow, and prognosis assessment of acute lymphoblastic leukemia (ALL). However, due to the nature of ALL, CC often encounters difficulties of complex karyotype, poor chromosome morphology, low mitotic index, or normal cells dividing only. In contrast, chromosomal microarray analysis (CMA) showed a specificity >99% and a sensitivity of 100% in chronic lymphocytic leukemia (CLL) patients. Here, we report our experience with CMA on adult ALL patients. Methods Thirty‐three bone marrow/blood samples from ALL patients (aged 18‐79 years, median 44) at diagnosis/relapse, analyzed by CC and/or fluorescence in situ hybridization (FISH), were recruited. Chromosomal microarray analysis results were compared with CC. Fluorescence in situ hybridization analysis, if available, was applied when there was a discrepancy. Results Copy‐neutral loss‐of‐heterozygosity (CN‐LOH) was found in 8 cases (24.2%). Only CN‐LOH at 9p was recurrent (3 cases, 9.1%). Copy number alterations (CNAs) were detected in 6 of 9 cases (66.7%) with normal karyotypes, in 3 of 5 cases (60.0%) with sole “balanced” translocations, and in 18 of 19 cases (94.7%) with complex karyotypes. Common CNAs involved CDKN2A/2B (30.3%), IKZF1 (27.3%), PAX5 (9.1%), RB1 (9.1%), BTG1 (6.7%), and ETV6 (6.7%), which regulate cell cycle, B lymphopoiesis, or act as tumor suppressors in ALL. Copy number alteration detection rate by CMA was 81.8% (27 of 33 cases) as compared to 57.6% (19 of 33 cases) by CC. Conclusion Incorporation of CMA as a routine clinical test at the time of diagnosis/relapse, in conjunction with CC and/or FISH, is highly recommended.

Integrated Genomic Analysis of Chromosomal Alterations and Mutations in B-Cell Acute Lymphoblastic Leukemia Reveals Distinct Genetic Profiles at Relapse

“…Similarly, as seen in previous studies, the frequency of IKZF1 deletions was higher in adults than in children [38]. IKZF1 deletions have been associated with a higher risk of relapse in ALL and have been shown to be a hallmark of BCR-ABL1-positive ALL, although they have also been identified in a fraction of BCR-ABL1-negative ALL patients [10,[38][39][40][41][42][43], as noted in our study. In recent years, IKZF1 deletions and TP53 alterations are being recognized as important markers of poor prognosis in ALL after a first relapse, mainly in children [9,39,44].…”

“…However, the mechanisms that probably fuel an ALL relapse are not fully understood. A combined analysis of gene mutations and copy number alterations (CNAs) could provide valuable insight into the discovery of the patterns of clonal evolution and the biomarkers that predict a greater likelihood of relapse in ALL [3,10,11]. Here, we have performed an integrated and sequential genomic analysis combining next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA) to identify the clonal shifts related to ALL progression.…”

Integrated Genomic Analysis of Chromosomal Alterations and Mutations in B-Cell Acute Lymphoblastic Leukemia Reveals Distinct Genetic Profiles at Relapse

“…However, the mechanisms that probably fuel an ALL relapse are not fully understood. A combined analysis of gene mutations and copy number alterations (CNAs) could provide valuable insight into the discovery of the patterns of clonal evolution and the biomarkers that predict a greater likelihood of relapse in ALL [3,10,11]. Here, we have performed an integrated and sequential genomic analysis combining next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA) to identify the clonal shifts related to ALL progression.…”

Loss of Heterozygosity in the Tumor DNA of De Novo Diagnosed Patients Is Associated with Poor Outcome for B-ALL but Not for T-ALL

“…One can conclude that STR analysis is an effective, easy, and low-cost tool for detecting LOH in ALL patients, although it is limited by incomplete coverage by common STR panels. In contrast, CMA with single nucleotide polymorphism (SNP) probes has more extensive coverage and has proven its effectiveness in identifying both copy number alterations and copy neutral LOH [ 28 , 29 , 30 , 31 , 32 ]. Thus, CMA can provide clinically significant information that complements cytogenetic analysis.…”