TY  - JOUR
AU  - Lee, Olivia W
AU  - Rodrigues, Calvin
AU  - Lin, Shu-Hong
AU  - Luo, Wen
AU  - Jones, Kristine
AU  - Brown, Derek W
AU  - Zhou, Weiyin
AU  - Karlins, Eric
AU  - Khan, Sairah M
AU  - Baulande, Sylvain
AU  - Raynal, Virginie
AU  - Surdez, Didier
AU  - Reynaud, Stephanie
AU  - Rubio, Rebeca Alba
AU  - Zaidi, Sakina
AU  - Grossetête, Sandrine
AU  - Ballet, Stelly
AU  - Lapouble, Eve
AU  - Laurence, Valérie
AU  - Pierron, Gaelle
AU  - Gaspar, Nathalie
AU  - Corradini, Nadège
AU  - Marec-Bérard, Perrine
AU  - Rothman, Nathaniel
AU  - Dagnall, Casey L
AU  - Burdett, Laurie
AU  - Manning, Michelle
AU  - Wyatt, Kathleen
AU  - Yeager, Meredith
AU  - Chari, Raj
AU  - Leisenring, Wendy M
AU  - Kulozik, Andreas E
AU  - Kriebel, Jennifer
AU  - Meitinger, Thomas
AU  - Strauch, Konstantin
AU  - Kirchner, Thomas
AU  - Dirksen, Uta
AU  - Mirabello, Lisa
AU  - Tucker, Margaret A
AU  - Tirode, Franck
AU  - Armstrong, Gregory T
AU  - Bhatia, Smita
AU  - Robison, Leslie L
AU  - Yasui, Yutaka
AU  - Romero-Pérez, Laura
AU  - Hartmann, Wolfgang
AU  - Metzler, Markus
AU  - Diver, W Ryan
AU  - Lori, Adriana
AU  - Freedman, Neal D
AU  - Hoover, Robert N
AU  - Morton, Lindsay M
AU  - Chanock, Stephen J
AU  - Grünewald, Thomas
AU  - Delattre, Olivier
AU  - Machiela, Mitchell J
TI  - Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding.
JO  - The American journal of human genetics
VL  - 110
IS  - 3
SN  - 0002-9297
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2023-00351
SP  - 427-441
PY  - 2023
N1  - 2023 Mar 2;110(3):427-441
AB  - Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.
KW  - 6p25.1 (Other)
KW  - EWSR1-FLI1 (Other)
KW  - Ewing sarcoma (Other)
KW  - GGAA microsatellite (Other)
KW  - GWAS (Other)
KW  - RREB1 (Other)
KW  - germline somatic interaction (Other)
KW  - long-read sequencing (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36787739
DO  - DOI:10.1016/j.ajhg.2023.01.017
UR  - https://inrepo02.dkfz.de/record/270998
ER  -