High-resolution structural variant profiling of myelodysplastic syndromes by optical genome mapping uncovers cryptic aberrations of prognostic and therapeutic significance

Leukemia, Journal Year: 2022, Volume and Issue: 36(9), P. 2306 - 2316

Published: Aug. 1, 2022

Chromosome banding analysis (CBA) remains the standard-of-care for structural variant (SV) assessment in MDS. Optical genome mapping (OGM) is a novel, non-sequencing-based technique high-resolution genome-wide SV profiling (SVP). We explored clinical value of SVP by OGM 101 consecutive, newly diagnosed MDS patients from single-center, who underwent cytogenetic and targeted NGS studies. detected 383 clinically significant, recurrent novel SVs. Of these, 224 (51%) SVs, seen across 34% patients, were cryptic CBA (included rearrangements involving MECOM, NUP98::PRRX2, KMT2A partial tandem duplications among others). decreased proportion normal karyotype 16%, identified complex genomes (17%), chromothripsis (6%) generated informative results both with insufficient metaphases. Precise gene/exon-level allowed relevant biomarkers (TP53 allele status, KMT2A-PTD) without additional testing. data was complementary to NGS. When applied retrospect, changed comprehensive scoring system (CCSS) R-IPSS risk-groups 21% 17% respectively an improved prediction prognosis. By multivariate analysis, CCSS only (not CBA), TP53 mutation BM blasts independently predicted survival. This first largest study reporting combined prognostication.

Language: Английский

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Optical genome mapping in acute myeloid leukemia: a multicenter evaluation

Blood Advances, Journal Year: 2022, Volume and Issue: 7(7), P. 1297 - 1307

Published: Nov. 24, 2022

Detection of hallmark genomic aberrations in acute myeloid leukemia (AML) is essential for diagnostic subtyping, prognosis, and patient management. However, cytogenetic/cytogenomic techniques used to identify those aberrations, such as karyotyping, fluorescence situ hybridization (FISH), or chromosomal microarray analysis (CMA), are limited by the need skilled personnel well significant time, cost, labor. Optical genome mapping (OGM) provides a single, cost-effective assay with significantly higher resolution than karyotyping comprehensive genome-wide comparable CMA added unique ability detect balanced structural variants (SVs). Here, we report real-world setting performance OGM cohort 100 AML cases that were previously characterized karyotype alone FISH CMA. identified all clinically relevant SVs copy number (CNVs) reported these standard cytogenetic methods when representative clones present >5% allelic fraction. Importantly, information 13% had been missed routine methods. Three normal karyotypes shown have cryptic translocations involving gene fusions. In 4% cases, findings would altered recommended clinical management, an additional 8% rendered potentially eligible trials. The results from this multi-institutional study indicate effectively recovers CNVs found standard-of-care reveals not reported. Furthermore, minimizes labor-intensive multiple tests while concomitantly maximizing detection through standardized workflow.

Language: Английский

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Multisite Assessment of Optical Genome Mapping for Analysis of Structural Variants in Constitutional Postnatal Cases

Journal of Molecular Diagnostics, Journal Year: 2023, Volume and Issue: 25(3), P. 175 - 188

Published: Feb. 22, 2023

This study compares optical genome mapping (OGM) performed at multiple sites with current standard-of-care (SOC) methods used in clinical cytogenetics. included 50 negative controls and 359 samples from individuals (patients) suspected genetic conditions referred for cytogenetic testing. OGM was using the Saphyr system Bionano Access software version 1.7. Structural variants, including copy number aneuploidy, regions of homozygosity, were detected classified according to American College Medical Genetics Genomics guidelines. Repeated expansions FMR1 contractions facioscapulohumeral dystrophy 1 also analyzed. results compared SOC technical concordance, classification intrasite intersite reproducibility, ability provide additional, clinically relevant information. Across five testing sites, 98.8% (404/409) yielded successful data analysis interpretation. Overall, concordance detect previously reported 99.5% (399/401). The blinded variant agreement between 97.6% (364/373). Replicate 130 structural variations 100% concordant. On basis this demonstration analytic validity utility by multisite assessment, authors recommend technology as an alternative existing tests rapid detection diagnosis postnatal constitutional disorders.

Language: Английский

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Optical Genome Mapping for Cytogenetic Diagnostics in AML

Cancers, Journal Year: 2023, Volume and Issue: 15(6), P. 1684 - 1684

Published: March 9, 2023

The classification and risk stratification of acute myeloid leukemia (AML) is based on reliable genetic diagnostics. A broad expanding variety relevant aberrations are structural variants beyond single-nucleotide variants. Optical Genome Mapping an unbiased, genome-wide, amplification-free method for the detection In this review, current knowledge (OGM) with regard to diagnostics in hematological malignancies general, AML specific, summarized. Furthermore, review focuses ability OGM expand use cytogenetic perhaps even replace older techniques such as chromosomal-banding analysis, fluorescence situ hybridization, or copy number variation microarrays. Finally, compared amplification-based a brief outlook future directions given.

Language: Английский

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

American Journal of Hematology, Journal Year: 2024, Volume and Issue: 99(4), P. 642 - 661

Published: Jan. 2, 2024

Optical Genome Mapping (OGM) is rapidly emerging as an exciting cytogenomic technology both for research and clinical purposes. In the last 2 years alone, multiple studies have demonstrated that OGM not only matches diagnostic scope of conventional standard care testing but it also adds significant new information in certain cases. Since consolidates benefits costly laborious tests (e.g., karyotyping, fluorescence situ hybridization, chromosomal microarrays) a single cost-effective assay, many laboratories started to consider utilizing OGM. 2021, international working group early adopters who are experienced with routine patients hematological neoplasms formed consortium (International Consortium Hematologic Malignancies, henceforth "the Consortium") create consensus framework implementation setting. The focus provide guidance implementing three specific areas: validation, quality control analysis interpretation variants. complex variables, we felt by consolidating our collective experience, could practical useful tool uniform hematologic malignancies ultimate goal achieving globally accepted standards.

Language: Английский

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Optical genome mapping improves the accuracy of classification, risk stratification, and personalized treatment strategies for patients with acute myeloid leukemia

American Journal of Hematology, Journal Year: 2024, Volume and Issue: 99(10), P. 1959 - 1968

Published: July 17, 2024

Abstract Cytogenomic characterization is crucial for the classification and risk stratification of acute myeloid leukemia (AML), thereby facilitating therapeutic decision‐making. We examined clinical utility optical genome mapping (OGM) in 159 AML patients (103 newly diagnosed 56 refractory/relapsed), all whom also underwent chromosomal banding analysis (CBA), fluorescence situ hybridization, targeted next‐generation sequencing. OGM detected nearly clinically relevant cytogenetic abnormalities that SCG identified with >99% sensitivity, provided clonal burden was above 20%. additional cytogenomic aberrations and/or information on fusion genes 77 (48%) patients, including eight normal karyotypes four failed karyotyping. The most common alterations by included chromoanagenesis ( n = 23), KMT2A partial tandem duplication 11), rearrangements involving MECOM 7), NUP98 2), JAK2 other gene fusions 17 10 showing novel partners. pinpointed (11%) where were concurrently CBA. Overall, 24 (15%) exclusively had potential to alter classification, stratification, trial eligibility. emerges as a powerful tool identifying detecting subtle or cryptic may otherwise remain undetectable

Language: Английский

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Structural Variant Analysis of Complex Karyotype Myelodysplastic Neoplasia Through Optical Genome Mapping

Genes Chromosomes and Cancer, Journal Year: 2025, Volume and Issue: 64(1)

Published: Jan. 1, 2025

ABSTRACT Myelodysplastic neoplasia with complex karyotype (CK‐MDS) poses significant clinical challenges and is associated poor survival. Detection of structural variants (SVs) crucial for diagnosis, prognostication, treatment decision‐making in MDS. However, the current standard‐of‐care (SOC) cytogenetic testing, relying on karyotyping, often yields ambiguous results cases CK. Here, SV detection by novel optical genome mapping (OGM) technique was explored 15 CK‐MDS cases, which collectively harbored 85 chromosomes abnormalities reported SOC. Additionally, OGM utilized discovery SVs. Altogether, detected corresponding > 5 Mbp alterations 73 out SOC abnormalities, resulting an 86% concordance rate. provided further specification these revealing that 64% altered were affected multiple SVs or chromoanagenesis. Prominently, only 5% missing true monosomies. In addition, not as abnormal karyotyping 93% clinically relevant gene‐level information, such TP53 , MECOM NUP98 IKZF1 ETV6 . Analysis revealed two previously unreported gene‐fusions ( SCFD1::ZNF592 VPS8::LRBA ), both confirmed transcriptome sequencing. Furthermore, repositioning CCDC26 (8q24.21) identified a potential cause inappropriate gene activation affecting SOX7 respectively. This study shows can significantly enhance diagnostic analysis highlights utility identifying cancer genomes.

Language: Английский

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Optical Genome Mapping as an Alternative to FISH-Based Cytogenetic Assessment in Chronic Lymphocytic Leukemia

Cancers, Journal Year: 2023, Volume and Issue: 15(4), P. 1294 - 1294

Published: Feb. 17, 2023

The fluorescence in situ hybridization (FISH) technique plays an important role the risk stratification and clinical management of patients with chronic lymphocytic leukemia (CLL). For genome-wide analysis, FISH needs to be complemented other cytogenetic methods, including karyotyping and/or chromosomal microarrays. However, this is often not feasible a diagnostic setup. Optical genome mapping (OGM) novel for high-resolution detection structural variants (SVs), previous studies have indicated that OGM could serve as generic tool hematological malignancies. Herein, we report results from our study evaluating concordance standard-of-care 18 CLL samples. were fully concordant between these two techniques blinded comparison. Using silico dilution series, lowest limit was determined range 3 9% variant allele fractions. Genome-wide analysis by revealed additional (>1 Mb) aberrations 78% samples, both unbalanced balanced SVs. Importantly, also enabled clinically relevant complex karyotypes, undetectable FISH, three Overall, demonstrates potential first-tier test powerful SV analysis.

Language: Английский

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Feasibility of Optical Genome Mapping in Cytogenetic Diagnostics of Hematological Neoplasms: A New Way to Look at DNA

Diagnostics, Journal Year: 2023, Volume and Issue: 13(11), P. 1841 - 1841

Published: May 24, 2023

Optical genome mapping (OGM) is a new genome-wide technology that can reveal both structural genomic variations (SVs) and copy number (CNVs) in single assay. OGM was initially employed to perform assembly research, but it now more widely used study chromosome aberrations genetic disorders human cancer. One of the most useful applications hematological malignancies, where chromosomal rearrangements are frequent conventional cytogenetic analysis alone insufficient, necessitating further confirmation using ancillary techniques such as fluorescence situ hybridization, microarrays, or multiple ligation-dependent probe amplification. The first studies tested efficiency sensitivity for SV CNV detection, comparing heterogeneous groups lymphoid myeloid sample data with those obtained standard diagnostic tests. Most work based on this innovative focused myelodysplastic syndromes (MDSs), acute leukemia (AML), lymphoblastic (ALL), whereas little attention paid chronic lymphocytic (CLL) myeloma (MM), none lymphomas. showed be considered highly reliable method, concordant able detect novel clinically significant SVs, thus allowing better patient classification, prognostic stratification, therapeutic choices malignancies.

Language: Английский

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Optical Genome Mapping Identifies Novel Recurrent Structural Alterations in Childhood ETV6::RUNX1+ and High Hyperdiploid Acute Lymphoblastic Leukemia

HemaSphere, Journal Year: 2023, Volume and Issue: 7(8), P. e925 - e925

Published: July 17, 2023

The mutational landscape of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common pediatric cancer, is not fully described partially because commonly applied short-read next generation sequencing has a limited ability to identify structural variations. By combining comprehensive analysis variants (SVs), single-nucleotide (SNVs), and small insertions-deletions, new subtype-defining therapeutic targets may be detected. We analyzed somatic alterations in 60 patients diagnosed with BCP-ALL subtypes, ETV6::RUNX1 + classical hyperdiploid (HD), using conventional cytogenetics, single nucleotide polymorphism (SNP) array, whole exome (WES), novel optical genome mapping (OGM) technique. Ninety-five percent SVs detected by cytogenetics SNP-array were verified OGM. OGM an additional 677 identified methods, including (subclonal) IKZF1 deletions. Based on OGM, harbored 2.7 times more than HD BCP-ALL, mainly focal Besides known development genes ( ETV6 , PAX5 BTG1, CDKN2A ), we 19 recurrently altered regions (in n ≥ 3) 9p21.3 FOCAD/HACD4 8p11.21 IKBKB 1p34.3 ZMYM1 4q24 MANBA 8p23.1 MSRA 10p14 SFMBT2 as well ETV6::RUNX1+ subtype-specific (12p13.1 GPRC5A 12q24.21 MED13L 18q11.2 MIB1 20q11.22 NCOA6 )). 3 fusion SFMBT2::DGKD, PDS5B::STAG2, TDRD5::LPCAT2 for which sequence expression validated long-read transcriptome sequencing, respectively. WES double hits SNVs BTG1 STAG2 TBL1XR1 NSD2 ) same patient demonstrating power combined approach define genomic BCP-ALL.

Language: Английский

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