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Lee, O.W.* ; Rodrigues, C.* ; Lin, S.H.* ; Luo, W.* ; Jones, K.* ; Brown, D.W.* ; Zhou, W.* ; Karlins, E.* ; Khan, S.M.* ; Baulande, S.* ; Raynal, V.* ; Surdez, D.* ; Reynaud, S.* ; Rubio, R.A.* ; Zaidi, S.* ; Grossetete, S.* ; Ballet, S.* ; Lapouble, E.* ; Laurence, V.* ; Pierron, G.* ; Gaspar, N.* ; Corradini, N.* ; Marec-Bérard, P.* ; Rothman, N.* ; Dagnall, C.L.* ; Burdett, L.* ; Manning, M.* ; Wyatt, K.* ; Yeager, M.* ; Chari, R.* ; Leisenring, W.M.* ; Kulozik, A.E.* ; Kriebel, J. ; Meitinger, T. ; Strauch, K. ; Kirchner, T.* ; Dirksen, U.* ; Mirabello, L.* ; Tucker, M.A.* ; Tirode, F.* ; Armstrong, G.T.* ; Bhatia, S.* ; Robison, L.L.* ; Yasui, Y.* ; Romero-Pérez, L.* ; Hartmann, W.* ; Metzler, M.* ; Diver, W.R.* ; Lori, A.* ; Freedman, N.D.* ; Hoover, R.N.* ; Morton, L.M.* ; Chanock, S.J.* ; Grunewald, T.G.P.* ; Delattre, O.* ; Machiela, M.J.*

Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding.

Am. J. Hum. Genet. 110, 427-441 (2023)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords 6p25.1 ; Ewsr1-fli1 ; Ewing Sarcoma ; Ggaa Microsatellite ; Gwas ; Rreb1 ; Germline Somatic Interaction ; Long-read Sequencing; Transcription Factor; Racial-differences; Gene; Fusion; Translocation; Association; Mutations; Elements; Rreb1; Set
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 110, Issue: 3, Pages: 427-441 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)
Institute of Genetic Epidemiology (IGE)
POF-Topic(s) 30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504091-002
G-500700-001
G-504100-001
Grants NCI NIH HHS
DOI 10.1016/j.ajhg.2023.01.017
WOS ID 000982413800001
Scopus ID 85149204000
PubMed ID 36787739
Erfassungsdatum 2023-02-23
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