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@ARTICLE{Brandes:277759,
author = {D. Brandes and L. Yasin and K. Nebral and J. Ebler and D.
Schinnerl and D. Picard and A. K. Bergmann and J. Alam and
S. Köhrer and O. A. Haas and A. Attarbaschi and T.
Marschall and M. Stanulla and A. Borkhardt$^*$ and T.
Brozou$^*$ and U. Fischer$^*$ and R. Wagener$^*$},
title = {{O}ptical {G}enome {M}apping {I}dentifies {N}ovel
{R}ecurrent {S}tructural {A}lterations in {C}hildhood
{ETV}6::{RUNX}1+ and {H}igh {H}yperdiploid {A}cute
{L}ymphoblastic {L}eukemia.},
journal = {HemaSphere},
volume = {7},
number = {8},
issn = {2572-9241},
address = {[Philadelphia, Pennsylvania]},
publisher = {Wolters Kluwer Health},
reportid = {DKFZ-2023-01476},
pages = {e925},
year = {2023},
abstract = {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.},
cin = {ED01},
ddc = {610},
cid = {I:(DE-He78)ED01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37469802},
pmc = {pmc:PMC10353714},
doi = {10.1097/HS9.0000000000000925},
url = {https://inrepo02.dkfz.de/record/277759},
}