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

Media type: E-Article
Title: Optical Genome Mapping Identifies Novel Recurrent Structural Alterations in Childhood ETV6::RUNX1+ and High Hyperdiploid Acute Lymphoblastic Leukemia
Contributor: Brandes, Danielle; Yasin, Layal; Nebral, Karin; Ebler, Jana; Schinnerl, Dagmar; Picard, Daniel; Bergmann, Anke K.; Alam, Jubayer; Köhrer, Stefan; Haas, Oskar A.; Attarbaschi, Andishe; Marschall, Tobias; Stanulla, Martin; Borkhardt, Arndt; Brozou, Triantafyllia; Fischer, Ute; Wagener, Rabea
imprint: Wiley, 2023
Published in: HemaSphere
Language: English
DOI: 10.1097/hs9.0000000000000925
ISSN: 2572-9241
Origination:
Footnote:
Description: <jats:p>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, <jats:italic toggle="yes">ETV6::RUNX1</jats:italic>+ 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) <jats:italic toggle="yes">IKZF1</jats:italic> deletions. Based on OGM, <jats:italic toggle="yes">ETV6::RUNX1</jats:italic>+ BCP-ALL harbored 2.7 times more SVs than HD BCP-ALL, mainly focal deletions. Besides SVs in known leukemia development genes (<jats:italic toggle="yes">ETV6</jats:italic>, <jats:italic toggle="yes">PAX5</jats:italic>, <jats:italic toggle="yes">BTG1, CDKN2A</jats:italic>), we identified 19 novel recurrently altered regions (in n ≥ 3) including 9p21.3 (<jats:italic toggle="yes">FOCAD/HACD4</jats:italic>), 8p11.21 (<jats:italic toggle="yes">IKBKB</jats:italic>), 1p34.3 (<jats:italic toggle="yes">ZMYM1</jats:italic>), 4q24 (<jats:italic toggle="yes">MANBA</jats:italic>), 8p23.1 (<jats:italic toggle="yes">MSRA</jats:italic>), and 10p14 (<jats:italic toggle="yes">SFMBT2</jats:italic>), as well as <jats:italic toggle="yes">ETV6::RUNX1+</jats:italic> subtype-specific SVs (12p13.1 (<jats:italic toggle="yes">GPRC5A</jats:italic>), 12q24.21 (<jats:italic toggle="yes">MED13L</jats:italic>), 18q11.2 (<jats:italic toggle="yes">MIB1</jats:italic>), 20q11.22 (<jats:italic toggle="yes">NCOA6</jats:italic>)). We detected 3 novel fusion genes (<jats:italic toggle="yes">SFMBT2::DGKD, PDS5B::STAG2,</jats:italic> and <jats:italic toggle="yes">TDRD5::LPCAT2</jats:italic>), 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 (<jats:italic toggle="yes">ETV6</jats:italic>, <jats:italic toggle="yes">BTG1</jats:italic>, <jats:italic toggle="yes">STAG2</jats:italic>, <jats:italic toggle="yes">MANBA</jats:italic>, <jats:italic toggle="yes">TBL1XR1</jats:italic>, <jats:italic toggle="yes">NSD2</jats:italic>) in the same patient demonstrating the power of the combined approach to define the landscape of genomic alterations in BCP-ALL.</jats:p>
Access State: Open Access

Search in field:

Recently searched for: