Genomic analysis of adult B-ALL identifies potential markers of shorter survival

Patel, Shiven B.; Mason, Clinton C.; Glenn, Martha; Paxton, Christian N.; South, Sara T.; Cessna, Melissa H.; Asch, Julie; Cobain, Erin F.; Bixby, Dale; Smith, Lauren B.; Gastier‐Foster, Julie M.; Schiffman, Joshua D.; Miles, Rodney R.

doi:10.1016/j.leukres.2017.01.034

Cited by 17 publications

(12 citation statements)

References 62 publications

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“…IKZF1 and CDKN2A/B deletions are known to be associated with poor prognosis in pediatric and adult B-ALL populations [27][28][29] , mainly in the BCR-ABL1 B-ALL subpopulation. Our results suggest that, despite the low number of cases analyzed, CDKN2A/B deletions are markers of poor survival in B-other ALL, and the association between CDKN2A/B and IKZF1 deletions might also contribute to the dismal prognosis of BCR-ABL1-like.…”

Section: Discussionmentioning

confidence: 99%

A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics

et al. 2020

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BCR-ABL1-like B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains poorly characterized in adults. We sought to establish the frequency and outcome of adolescent and adult BCR-ABL1-like ALL using a novel RNA-Seq signature in a series of patients with BCP-ALL. To this end, we developed and tested an RNA-Seq custom panel of 42 genes related to a BCR-ABL1-like signature in a cohort of 100 patients with BCP-ALL and treated with risk-adapted ALL trials. Mutations related to BCR-ABL1-like ALL were studied in a panel of 33 genes by next-generation sequencing (NGS). Also, CRLF2 overexpression and IKZF1/CDKN2A/B deletions were analyzed. Twenty out of 79 patients (12-84 years) were classified as BCR-ABL1-like (25%) based on heatmap clustering, with significant overexpression of ENAM, IGJ, and CRLF2 (P ≤ 0.001). The BCR-ABL1-like subgroup accounted for 29% of 15-60-year-old patients, with the following molecular characteristics: CRLF2 overexpression (75% of cases), IKZF1 deletions (64%), CDKN2A/B deletions (57%), and JAK2 mutations (57%). Among patients with postinduction negative minimal residual disease, those with the BCR-ABL1like ALL signature had a higher rate of relapse and lower complete response duration than non-BCR-ABL1-like patients (P = 0.007). Thus, we have identified a new molecular signature of BCR-ABL1-like ALL that correlates with adverse prognosis in adult patients with ALL.

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Section: Discussionmentioning

confidence: 99%

A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics

et al. 2020

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“…The literature screening process is shown as a flow diagram in Figure 1. Finally, 13 studies with a total number of 2857 patients were included in this metaanalysis [14][15][16][17][18][21][22][23][24][25][26][27][28]. These studies were published between 2005 and 2018 and the sample size ranged from 54 to 864 with a median of 81.…”

Section: Study Selection and Characteristicsmentioning

confidence: 99%

Prognostic significance of CDKN2A/B deletions in acute lymphoblastic leukaemia: a meta-analysis

2019

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Background: Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) genes are frequently altered in acute lymphoblastic leukaemia (ALL) patients. The aim of this meta-analysis was to comprehensively assess the prognostic value of CDKN2A/B deletions in ALL patients. Methods: Systematic literature review was conducted in PubMed, Embase and Cochrane databases up to July 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Results: A total of thirteen studies including 2857 patients were eligible for this meta-analysis. Combined HRs suggested that CDKN2A/B deletions were poor prognostic factors for both overall survival (OS) (HR ¼ 2.15, 95% CI 1.82-2.54) and event-free survival (EFS)/disease-free survival (DFS)/relapse-free survival (RFS) (HR ¼ 2.16, 95% CI 1.73-2.69). The adverse impact remained significant in both adult and paediatric ALL patients, and also in subgroups by ethnicity, ALL type, detection method of CDKN2A/B deletions, statistical method and endpoint. Conclusions: Our findings suggested that CDKN2A/B deletions were associated with poor prognosis independently in both adult and childhood ALL patients. Inclusion of CDKN2A/B status may further improve the risk stratification of ALL patients. KEY MESSAGESAlthough numerous studies have explored the prognostic significance of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions in acute lymphoblastic leukaemia (ALL) patients, the results remain conflicting. In this meta-analysis, we found that CDKN2A/B deletions were independent poor prognostic markers for both adult and paediatric ALL patients. Our findings justify the inclusion of CDKN2A/B status in the risk stratification of ALL patients.

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“…These studies also showed that the relapse clone was already present at diagnosis as a minor subpopulation in most cases and that the elimination of the major clone at diagnosis favored the expansion of the remaining clones. Regarding adult relapsed ALL, the number of genetic studies is more scarce . Although the low number of paired diagnosis and relapsed samples does not allow solid conclusions to be drawn, the clonal dynamics in adult relapsed ALL resemble that observed in childhood ALL.…”

Section: Introductionmentioning

confidence: 99%

Copy number profiling of adult relapsed B‐cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms

Ribera

Zamora

Morgades

et al. 2017

Genes Chromosomes & Cancer

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The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays. A trend to acquire homozygous CDKN2A/B deletions and a significant increase in the number of copy number alterations (CNA) was observed from diagnosis to first relapse. Evolution from an ancestral clone was the main pattern of clonal evolution. Relapse samples were extremely heterogeneous regarding CNA frequencies. However, CDKN2A/B, PAX5, ETV6, ATM, IKZF1, VPREB1, and TP53 deletions and duplications of 1q, 8q, 17q, 21, X/Y PAR1, and Xp were frequently detected at relapse. Duplications of genes involved in cell proliferation, drug resistance and stem cell homeostasis regulation, as well as deletions of KDM6A and STAG2 genes emerged as specific alterations at relapse. Genomics of relapsed adult B-cell precursor ALL is highly heterogeneous, although some recurrent lesions involved in essential pathways deregulation were frequently observed. Selective and simultaneous targeting of these deregulated pathways may improve the results of current salvage therapies.

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Genomic analysis of adult B-ALL identifies potential markers of shorter survival

Cited by 17 publications

References 62 publications

A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics

A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics

Prognostic significance of CDKN2A/B deletions in acute lymphoblastic leukaemia: a meta-analysis

Copy number profiling of adult relapsed B‐cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms

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