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

Autor:	Brandes D; Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University and University Hospital Dusseldorf, Germany.; Dusseldorf School of Oncology (DSO), Medical Faculty, Heinrich-Heine University, Dusseldorf, Germany., Yasin L; Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University and University Hospital Dusseldorf, Germany., Nebral K; Labdia Labordiagnostik, Clinical Genetics, Vienna, Austria.; St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria., Ebler J; Institute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich-Heine University, Dusseldorf, Germany.; Center for Digital Medicine, Heinrich-Heine University, Dusseldorf, Germany., Schinnerl D; St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria., Picard D; Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University and University Hospital Dusseldorf, Germany., Bergmann AK; Institute of Human Genetics, Hannover Medical School (MHH), Hannover, Germany., Alam J; Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University and University Hospital Dusseldorf, Germany., Köhrer S; Labdia Labordiagnostik, Clinical Genetics, Vienna, Austria.; St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria., Haas OA; St. Anna Children's Hospital, Department of Pediatric Hematology/Oncology, Pediatric Clinic, Medical University, Vienna, Austria., Attarbaschi A; St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria.; St. Anna Children's Hospital, Department of Pediatric Hematology/Oncology, Pediatric Clinic, Medical University, Vienna, Austria., Marschall T; Institute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich-Heine University, Dusseldorf, Germany.; Center for Digital Medicine, Heinrich-Heine University, Dusseldorf, Germany., Stanulla M; Pediatric Hematology and Oncology, Hannover Medical School (MHH), Hannover, Germany., Borkhardt A; Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University and University Hospital Dusseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, Germany., Brozou T; Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University and University Hospital Dusseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, Germany., Fischer U; Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University and University Hospital Dusseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, Germany., Wagener R; Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University and University Hospital Dusseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, Germany.
Jazyk:	angličtina
Zdroj:	HemaSphere [Hemasphere] 2023 Jul 17; Vol. 7 (8), pp. e925. Date of Electronic Publication: 2023 Jul 17 (Print Publication: 2023).
DOI:	10.1097/HS9.0000000000000925
Abstrakt:	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 of structural variants (SVs), single-nucleotide variants (SNVs), and small insertions-deletions, new subtype-defining and therapeutic targets may be detected. We analyzed the landscape of somatic alterations in 60 pediatric patients diagnosed with the most common BCP-ALL subtypes, ETV6::RUNX1 + and classical hyperdiploid (HD), using conventional cytogenetics, single nucleotide polymorphism (SNP) array, whole exome sequencing (WES), and the novel optical genome mapping (OGM) technique. Ninety-five percent of SVs detected by cytogenetics and SNP-array were verified by OGM. OGM detected an additional 677 SVs not identified using the conventional methods, including (subclonal) IKZF1 deletions. Based on OGM, ETV6::RUNX1 + BCP-ALL harbored 2.7 times more SVs than HD BCP-ALL, mainly focal deletions. Besides SVs in known leukemia development genes ( ETV6 , PAX5 , BTG1, CDKN2A ), we identified 19 novel recurrently altered regions (in n ≥ 3) including 9p21.3 ( FOCAD/HACD4 ), 8p11.21 ( IKBKB ), 1p34.3 ( ZMYM1 ), 4q24 ( MANBA ), 8p23.1 ( MSRA ), and 10p14 ( SFMBT2 ), as well as ETV6::RUNX1+ subtype-specific SVs (12p13.1 ( GPRC5A ), 12q24.21 ( MED13L ), 18q11.2 ( MIB1 ), 20q11.22 ( NCOA6 )). We detected 3 novel fusion genes ( SFMBT2::DGKD, PDS5B::STAG2, and TDRD5::LPCAT2 ), for which the sequence and expression were validated by long-read and whole transcriptome sequencing, respectively. OGM and WES identified double hits of SVs and SNVs ( ETV6 , BTG1 , STAG2 , MANBA , TBL1XR1 , NSD2 ) in the same patient demonstrating the power of the combined approach to define the landscape of genomic alterations in BCP-ALL. Competing Interests: The authors have no conflicts of interest to disclose. (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
Databáze:	MEDLINE
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