The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia.

Jonathan Lukas Lühmann,Gunnar Cario,Markéta Žaliová,Gudrun Göhring,Brigitte Schlegelberger,Marie Stelter,Anke Katharina Bergmann,Anja Möricke,Martin Stanulla,Maximilian Schieck,Martin Schrappe,Josephine Kater,Doris Steinemann,Marie Wolter,Jana Lentes

doi:10.3390/cancers13174388

Jonathan Lukas Lühmann, Gunnar Cario + Show 13 more

Open Access

https://doi.org/10.3390/cancers13174388

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Journal: Cancers	Publication Date: Aug 30, 2021
Citations: 39	License type: CC BY 4.0

Affiliation: Hannover Medical School, Kiel University, Charles University

Abstract

Acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer occurring in children. ALL is characterized by structural and numeric genomic aberrations that strongly correlate with prognosis and clinical outcome. Usually, a combination of cyto- and molecular genetic methods (karyotyping, array-CGH, FISH, RT-PCR, RNA-Seq) is needed to identify all aberrations relevant for risk stratification. We investigated the feasibility of optical genome mapping (OGM), a DNA-based method, to detect these aberrations in an all-in-one approach. As proof of principle, twelve pediatric ALL samples were analyzed by OGM, and results were validated by comparing OGM data to results obtained from routine diagnostics. All genomic aberrations including translocations (e.g., dic(9;12)), aneuploidies (e.g., high hyperdiploidy) and copy number variations (e.g., IKZF1, PAX5) known from other techniques were also detected by OGM. Moreover, OGM was superior to well-established techniques for resolution of the more complex structure of a translocation t(12;21) and had a higher sensitivity for detection of copy number alterations. Importantly, a new and unknown gene fusion of JAK2 and NPAT due to a translocation t(9;11) was detected. We demonstrate the feasibility of OGM to detect well-established as well as new putative prognostic markers in an all-in-one approach in ALL. We hope that these limited results will be confirmed with testing of more samples in the future.

Highlights

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, withB-cell precursor ALL (BCP-ALL) accounting for the majority of cases
We focus here on called structural variants (SV) and CNVs, which are known to be clinically relevant or which may be clinically relevant based on their frequency in reference genomes but we will not address polymorphic regions according to DGV
With the aim to test the feasibility of optical genome mapping (OGM) in the genetic classification of pediatric ALL, we selected genetically well-characterized ALL samples, which were intensively analyzed by well-established technologies (SNP-array, RNA-Seq, FISH, karyotyping, MLPA) used within our routine diagnostic workflow

Summary

Introduction

B-cell precursor ALL (BCP-ALL) accounting for the majority of cases. The aims to better understand cancer cell behavior and to further tailor treatment to individual patients require the precise determination of known genetic markers of relapse prediction and therapeutic decision making. The intensity of treatment is based on a patient’s risk to relapse, which is predicted by a combination of clinical (e.g., age, white blood cell count), cytogenetic, and morphological early response criteria. In addition to MRD, a broad spectrum of known underlying genetic aberrations is used for risk stratification. There are markers indicative for a favorable outcome, such as the ETV6/RUNX1 fusion that results from a t(12;21) rearrangement [9,10]. Treatment intensity strongly depends on these genetic stratification markers [11]

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