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@ARTICLE{Schpf:286658,
author = {J. Schöpf$^*$ and S. Uhrig$^*$ and C. Heilig$^*$ and K.
Lee$^*$ and T. Walther$^*$ and A. Carazzato$^*$ and A.
Dobberkau$^*$ and D. Weichenhan$^*$ and C. Plass$^*$ and M.
Hartmann$^*$ and G. D. Diwan and Z. Carrero$^*$ and C.
Ball$^*$ and T. Hohl$^*$ and T. Kindler$^*$ and P. S.
Rudolph-Hähnel$^*$ and D. Helm$^*$ and M. Schneider$^*$ and
A. Nilsson and I. Øra and R. Imle$^*$ and A. Banito$^*$ and
R. B. Russell and B. Jones$^*$ and D. Lipka$^*$ and H.
Glimm$^*$ and D. Hübschmann$^*$ and W. Hartmann and S.
Fröhling$^*$ and C. Scholl$^*$},
title = {{M}ulti-omic and functional analysis for classification and
treatment of sarcomas with {FUS}-{TFCP}2 or {EWSR}1-{TFCP}2
fusions.},
journal = {Nature Communications},
volume = {15},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {DKFZ-2024-00022},
pages = {51},
year = {2024},
note = {#EA:B290#EA:B340#LA:B290#LA:B340#},
abstract = {Linking clinical multi-omics with mechanistic studies may
improve the understanding of rare cancers. We leverage two
precision oncology programs to investigate rhabdomyosarcoma
with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without
effective therapies. All tumors exhibit outlier ALK
expression, partly accompanied by intragenic deletions and
aberrant splicing resulting in ALK variants that are
oncogenic and sensitive to ALK inhibitors. Additionally,
recurrent CKDN2A/MTAP co-deletions provide a rationale for
PRMT5-targeted therapies. Functional studies show that
FUS-TFCP2 blocks myogenic differentiation, induces
transcription of ALK and truncated TERT, and inhibits DNA
repair. Unlike other fusion-driven sarcomas,
TFCP2-rearranged tumors exhibit genomic instability and
signs of defective homologous recombination. DNA methylation
profiling demonstrates a close relationship with
undifferentiated sarcomas. In two patients, sarcoma was
preceded by benign lesions carrying FUS-TFCP2, indicating
stepwise sarcomagenesis. This study illustrates the
potential of linking precision oncology with preclinical
research to gain insight into the classification,
pathogenesis, and therapeutic vulnerabilities of rare
cancers.},
cin = {B290 / B340 / HD01 / B370 / B280 / DD01 / FM01 / W120 /
B380},
ddc = {500},
cid = {I:(DE-He78)B290-20160331 / I:(DE-He78)B340-20160331 /
I:(DE-He78)HD01-20160331 / I:(DE-He78)B370-20160331 /
I:(DE-He78)B280-20160331 / I:(DE-He78)DD01-20160331 /
I:(DE-He78)FM01-20160331 / I:(DE-He78)W120-20160331 /
I:(DE-He78)B380-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38168093},
doi = {10.1038/s41467-023-44360-2},
url = {https://inrepo02.dkfz.de/record/286658},
}