A framework for the clinical implementation of optical genome mapping in hematologic malignancies

Levy, Brynn; Kanagal‐Shamanna, Rashmi; Sahajpal, Nikhil S.; Neveling, Kornelia; Rack, Katrina; Dewaele, Barbara; Olde Weghuis, Daniel; Stevens‐Kroef, Marian; Puiggros, Anna; Mallo, Mar; Clifford, Benjamin; Mantere, Tuomo; Hoischen, Alexander; Espinet, Blanca; Kolhe, Ravindra; Solé, Francesc; Raca, Gordana; Smith, Adam C.

doi:10.1002/ajh.27175

Cited by 3 publications

(2 citation statements)

References 42 publications

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“…Furthermore, the development of optical genomic mapping (OGM) that uses chromosome band patterns from single DNA strands, assembled bioinformatically to identify genomic alterations at high resolution (de novo assembly: 500 bp), now offers efficient analysis of genetic alterations within a genome without sequencing [21]. Notably, OGM provides an effective tool to detect CNAs in cancer, as shown in haematological malignancies [22], and may represent a cost-effective option for genetic screening in future clinical settings [23]. Implementation of these new detection methods along with a plethora of novel bioinformatic tools has highlighted the role and incidence of CNAs in tumour development, maintenance and response to treatment, and in several cases, associated specific CNA/CNV with clinical outcomes, as further detailed below.…”

Section: Cna/cnv Detectionmentioning

confidence: 99%

Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer

Carey-Smith,

Kotecha,

Cheung

et al. 2024

IJMS

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Copy number alterations (CNAs), resulting from the gain or loss of genetic material from as little as 50 base pairs or as big as entire chromosome(s), have been associated with many congenital diseases, de novo syndromes and cancer. It is established that CNAs disturb the dosage of genomic regions including enhancers/promoters, long non-coding RNA and gene(s) among others, ultimately leading to an altered balance of key cellular functions. In cancer, CNAs have been associated with almost all steps of the disease: predisposition, initiation, development, maintenance, response to treatment, resistance, and relapse. Therefore, understanding how specific CNAs contribute to tumourigenesis may provide prognostic insight and ultimately lead to the development of new therapeutic approaches to improve patient outcomes. In this review, we provide a snapshot of what is currently known about CNAs and cancer, incorporating topics regarding their detection, clinical impact, origin, and nature, and discuss the integration of innovative genetic engineering strategies, to highlight the potential for targeting CNAs using novel, dosage-sensitive and less toxic therapies for CNA-driven cancer.

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Section: Cna/cnv Detectionmentioning

confidence: 99%

Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer

Carey-Smith,

Kotecha,

Cheung

et al. 2024

IJMS

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“…To provide guidance for the clinical implementation of OGM, the International Consortium for Optical Genome Mapping in Hematologic Malignancies has recently authored a framework for the clinical implementation of OGM in hematologic malignancies (Levy et al 2024). This guidance has been assembled by a consortium of early adopters of OGM, who have successfully implemented the technology in their clinical laboratories.…”

Section: Introductionmentioning

confidence: 99%

Optical Genome Mapping improves detection and streamlines analysis of structural variants in myeloid neoplasms

Raca,

Sahoo,

Anwar Iqbal

et al. 2024

Preprint

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Accurate diagnosis and risk stratification of hematological malignancies require disease-specific laboratory testing procedures involving the use of hematopathology, flow cytometry, molecular, and cytogenetic testing. While individual laboratories develop unique workflows to accommodate volume, clinical needs, and staffing, cytogenetic laboratories generally require a multitude of targeted and genome-wide tests that detect clinically relevant aberrations in hematologic malignancies. Specifically, the frequent use of multiple FISH panels coupled with concurrent chromosome analysis, can be both labor, and resource intensive. Optical Genome Mapping (OGM) is a comprehensive cytogenetic solution for detecting structural variants with high resolution and increased accuracy for hematological malignancy subtypes at the DNA level without need of any cell culture regimens. A new software tool for analysis of OGM data called VIA (Variant Intelligence Applications), provides an integrative analysis, interpretation, and reporting solution for OGM and other datatypes. In this study, we performed retrospective review of 56 datasets, representing 10 unique myeloid cases to assess multi-user (technologist and laboratory director) analyses and classification. Interpretation and reporting of OGM results were 100% concordant between reviewers for four cases with negative results by standard of care (SOC) testing. For the other six cases, five pathognomonic gene fusions identified by SOC assays were unanimously reported as Tier 1A classification was unanimous for five sentinel gene fusion rearrangements identified by SOC. OGM also found additional structural variants of clinical relevance in five of the six cases that were not found by SOC methods. Leveraging automatic pre-classification of variants and a custom decision tree, the VIA software enabled complete analysis with a mean technologist review time (variant analysis and initial tier determination) of 30.7 minutes. The analysis, interpretation, and reporting workflow described in this pilot study provides a framework for standardized and streamlined reporting of clinically significant variant in myeloid malignancies using VIA.

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Genomic Characterization of Partial Tandem Duplication Involving the KMT2A Gene in Adult Acute Myeloid Leukemia

Seto,

Downs,

King

et al. 2024

Cancers

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Background: Gene rearrangements affecting KMT2A are frequent in acute myeloid leukemia (AML) and are often associated with a poor prognosis. KMT2A gene fusions are often detected by chromosome banding analysis and confirmed by fluorescence in situ hybridization. However, small intragenic insertions, termed KMT2A partial tandem duplication (KMT2A-PTD), are particularly challenging to detect using standard molecular and cytogenetic approaches. Methods: We have validated the use of a custom hybrid-capture-based next-generation sequencing (NGS) panel for comprehensive profiling of AML patients seen at our institution. This NGS panel targets the entire consensus coding DNA sequence of KMT2A. To deduce the presence of a KMT2A-PTD, we used the relative ratio of KMT2A exons coverage. We sought to corroborate the KMT2A-PTD NGS results using (1) multiplex-ligation probe amplification (MLPA) and (2) optical genome mapping (OGM). Results: We analyzed 932 AML cases and identified 41 individuals harboring a KMT2A-PTD. MLPA, NGS, and OGM confirmed the presence of a KMT2A-PTD in 22 of the cases analyzed where orthogonal testing was possible. The two false-positive KMT2A-PTD calls by NGS could be explained by the presence of cryptic structural variants impacting KMT2A and interfering with KMT2A-PTD analysis. OGM revealed the nature of these previously undetected gene rearrangements in KMT2A, while MLPA yielded inconclusive results. MLPA analysis for KMT2A-PTD is limited to exon 4, whereas NGS and OGM resolved KMT2A-PTD sizes and copy number levels. Conclusions: KMT2A-PTDs are complex gene rearrangements that cannot be fully ascertained using a single genomic platform. MLPA, NGS panels, and OGM are complementary technologies applied in standard-of-care testing for AML patients. MLPA and NGS panels are designed for targeted copy number analysis; however, our results showed that integration of concurrent genomic alterations is needed for accurate KMT2A-PTD identification. Unbalanced chromosomal rearrangements overlapping with KMT2A can interfere with the diagnostic sensitivity and specificity of copy-number-based KMT2A-PTD detection methodologies.

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A framework for the clinical implementation of optical genome mapping in hematologic malignancies

Cited by 3 publications

References 42 publications

Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer

Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer

Optical Genome Mapping improves detection and streamlines analysis of structural variants in myeloid neoplasms

Genomic Characterization of Partial Tandem Duplication Involving the KMT2A Gene in Adult Acute Myeloid Leukemia

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