Abstract
The clonal basis of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is complex and not fully understood. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA) were carried out in matched diagnosis–relapse samples from 13 BCP-ALL patients to identify patterns of genetic evolution that could account for the phenotypic changes associated with disease relapse. The integrative genomic analysis of aCGH, MLPA and NGS revealed that 100% of the BCP-ALL patients showed at least one genetic alteration at diagnosis and relapse. In addition, there was a significant increase in the frequency of chromosomal lesions at the time of relapse (p = 0.019). MLPA and aCGH techniques showed that IKZF1 was the most frequently deleted gene. TP53 was the most frequently mutated gene at relapse. Two TP53 mutations were detected only at relapse, whereas the three others showed an increase in their mutational burden at relapse. Clonal evolution patterns were heterogeneous, involving the acquisition, loss and maintenance of lesions at relapse. Therefore, this study provides additional evidence that BCP-ALL is a genetically dynamic disease with distinct genetic profiles at diagnosis and relapse. Integrative NGS, aCGH and MLPA analysis enables better molecular characterization of the genetic profile in BCP-ALL patients during the evolution from diagnosis to relapse.
Highlights
Acute lymphoblastic leukemia (ALL) is a disease with specific genetic alterations associated with drug resistance, treatment failure and disease relapse [1,2]
Our integrative multiplex ligation-dependent probe amplification (MLPA)–array comparative genomic hybridization (aCGH) analysis showed that the percentages of deleted genes in the following paired diagnosis/relapse B-cell precursor acute lymphoblastic leukemia (BCP-ALL) samples were: IKZF1, 54% vs. 62%, p = 0.691; CDKN2A/B, 54% vs. 23%, p = 0.107; PAX5, 38% vs. 23%, p = 0.673; EBF1, 23% vs. 15%, p = 1.000; BTG1, 23% vs
Our integrative MLPA–aCGH analysis showed that the percentages of deleted genes in the following paired diagnosis/relapse BCP-ALL samples were: IKZF1, 54% vs. 62%, p = 0.691; CDKN2A/B, 54% vs. 23%, p = 0.107; PAX5, 38% vs. 23%, p = 0.673; EBF1, 23% vs. 15%, p = 1.000; BTG1, 23% vs. 23%, p = 1.000; ETV6, 15% vs. 15%, p = 1.000; RB1, 8% vs. 15%, p = 1.000, and PAR1, 15% vs
Summary
Acute lymphoblastic leukemia (ALL) is a disease with specific genetic alterations associated with drug resistance, treatment failure and disease relapse [1,2]. Genomic studies of matched diagnosis–relapse samples from ALL patients have shed light on the clonal evolution that leads to relapse, the pathways associated with chemoresistance, and the potential targets for therapy [4,5,6,7,8,9]. 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]. 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
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