An integrated genomic profile that includes copy number alterations is highly predictive of minimal residual disease status in childhood precursor B-lineage acute lymphoblastic leukemia

Patkar, Nikhil; Subramanian, Papagudi Ganesan; Tembhare, Prashant; Mandalia, Sneha; Chaterjee, Gaurav; Rabade, Nikhil; Kodgule, Rohan; Chopra, Karishma; Bibi, Asma; Joshi, Shalik Ram; Mascerhenas, Russel; Kadam-Amare, Pratibha; Narula, Gaurav; Arora, Brijesh; Banavali, Shripad; Gujral, Sumeet

doi:10.4103/ijpm.ijpm_466_16

Cited by 12 publications

(4 citation statements)

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“…Distinct CNA profiles were evident in B-ALL and T-ALL with both mutually exclusive and co-occurring genes. The dominance pattern of key genes affected in B-ALL cases was similar to earlier studies from India ( IKZF1, CDKN2A/B, PAX5, ETV6 ) (8, 9, 12) and different from that reported by other groups where deletions in CDKN2A/B and ETV6 were dominant (6). The new gene targets such as BTLA, CD200, VPREB1 which are associated with inferior event-free and overall survival; DMD with relapse, TBL1XR1 and TP53 with chemo-resistance; EZH2 , PAR1 region, and P2RY8-CRLF2 with poor prognosis; CASP8AP2, NF1 , and SUZ12 associated with poor response to induction therapy are included in this dMLPA panel and useful for further risk stratification in cytogenetically good risk B-ALL cases.…”

Section: Discussionsupporting

confidence: 85%

“…Also, deletions of IKZF1 exon 4–8 associated with poor outcome although are rare but were seen in two of our samples in which this gene was affected. Earlier studies have reported the prognostic relevance of deletions in IKZF1 and EBF1 genes which are associated with MRD positivity (6, 9, 12). In our retrospective study, since IKZF1 deletions were primarily detected in BCR-ABL1 positive B-ALL cases, these cases were risk stratified into the poor risk category and were given intensive chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…The specific genetic subtypes in B-ALL are associated with distinct prognostic outcomes e.g., t(9;22) BCR-ABL1 translocation, MLL gene rearrangements, hypodiploidy, and intrachromosomal amplification of chromosome 21 ( iAMP21 ) predict poor outcome and genetic hallmarks such as ETV6-RUNX1 and hyperdiploid ALL predict favorable outcome (1, 5). An integrated cytogenetic and molecular genetics approach has been proposed and validated in small cohorts for improved risk stratification in B-ALL and classification of patients into clinically relevant subtypes with potentially important implications for therapy (6–9). In addition to gross chromosomal rearrangements, partial, or complete deletions of the IKZF1, CDKN2A/B, EBF1 , and RB1 genes have emerged as independent predictors of poor outcome in B-ALL (10–12).…”

Section: Introductionmentioning

confidence: 99%

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Rapid Identification of Key Copy Number Alterations in B- and T-Cell Acute Lymphoblastic Leukemia by Digital Multiplex Ligation-Dependent Probe Amplification

et al. 2019

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Recurrent clonal genetic alterations are the hallmark of Acute Lymphoblastic Leukemia (ALL) and govern the risk stratification, response to treatment and clinical outcome. In this retrospective study conducted on ALL patient samples, the purpose was to estimate the copy number alterations (CNAs) in ALL by digitalMLPA (dMLPA), validation of the dMLPA data by conventional MLPA and RT-PCR, and correlation of CNAs with Minimal Residual Disease (MRD) status. The ALL patient samples (n = 151; B-ALL, n = 124 cases and T-ALL, n = 27 cases) were assessed for CNAs by dMLPA for detection of sub-microscopic CNAs and ploidy status. This assay allowed detection of ploidy changes and CNAs by multiplexing of karyotyping probes and probes covering 54 key gene targets implicated in ALL. Using the dMLPA assay, CNAs were detected in ~89% (n = 131) of the cases with 66% of the cases harboring ≥3 CNAs. Deletions in CDKN2A/B, IKZF1, and PAX5 genes were detectable in a quarter of these cases. Heterozygous and homozygous gene deletions, and duplications were observed in genes involved in cell cycle control, tumor suppression, lineage differentiation, lymphoid signaling, and transcriptional regulators with implications in treatment response and survival outcome. Distinct CNAs profiles were evident in B-ALL and T-ALL cases. Additionally, the dMLPA assay could reliably identify ploidy status and copy number-based gene fusions (SIL-TAL1, NUP214-ABL, EBF1-PDGFRB). Cases of B-ALL with no detectable recurrent genetic abnormalities could potentially be risk stratified based on the CNA profile. In addition to the commonly used gene deletions for risk assessment (IKZF1, EBF1, CDKN2A/B), we identified a broader spectrum of gene alterations (gains of- RUNX1, LEF1, NR3C2, PAR1, PHF6; deletions of- NF1, SUZ12, MTAP) that significantly correlated with the status of MRD clearance. The CNAs detected by dMLPA were validated by conventional MLPA and showed high concordance (r = 0.99). Our results demonstrated dMLPA to be a robust and reliable alternative for rapid detection of key CNAs in newly diagnosed ALL patients. Integration of ploidy status and CNAs detected by dMLPA with cytogenetic and clinical risk factors holds great potential in further refinement of patient risk stratification and response to treatment in ALL.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rapid Identification of Key Copy Number Alterations in B- and T-Cell Acute Lymphoblastic Leukemia by Digital Multiplex Ligation-Dependent Probe Amplification

et al. 2019

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“…In pediatric ALL, MRD post induction range between 25-30% (Borowitz et al, 2008;Patkar et al, 2017), in our study 13 out of 46 patients (28%) had positive MRD post induction, furthermore MRD positivity is demonstrable in 14 out of 32 patients (43.8%), and 10 out of 28 patients (35.7%) at 6 and 12 months; respectively.…”

Section: Discussionsupporting

confidence: 54%

Minimal Residual Disease in Adult Acute Lymphoblastic Leukemia: Egyptian Experience

Ibrahim

Saeed

2022

Asian Pac J Cancer Prev

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Recently, it has shown more extensive application in adult ALL. This allows better characterization of ALL patients and segregation according to their MRD status into risk groups allowing for the individualization of treatment decisions. Low risk group exhibits MRD negativity and may benefit from treatment reduction limiting toxicity from chemotherapeutic regimens, whereas high risk group with positive MRD may need treatment intensification. Moreover, MRD diagnostics are used in the assessment of efficacy of novel agents like monoclonal antibodies and CAR T-cell therapy (van Dongen et al., 2015).Minimal residual disease measurement in ALL patients has been performed by either multi-parameter

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Pediatric Acute Leukemias

Narula,

Moulik,

Dhamne

et al. 2024

Tata Memorial Centre Textbook of Oncology

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An integrated genomic profile that includes copy number alterations is highly predictive of minimal residual disease status in childhood precursor B-lineage acute lymphoblastic leukemia

Abstract: These data seem to indicate that in addition to cytogenetics, CNA should be incorporated into routine clinical testing and risk algorithms for B-ALL. The IGC is of prognostic relevance and offers an additional avenue for prognostication and risk-adapted therapy.

Cited by 12 publications

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Rapid Identification of Key Copy Number Alterations in B- and T-Cell Acute Lymphoblastic Leukemia by Digital Multiplex Ligation-Dependent Probe Amplification

Rapid Identification of Key Copy Number Alterations in B- and T-Cell Acute Lymphoblastic Leukemia by Digital Multiplex Ligation-Dependent Probe Amplification

Minimal Residual Disease in Adult Acute Lymphoblastic Leukemia: Egyptian Experience

Pediatric Acute Leukemias

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