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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)
DOI PMC
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
Corresponding Author
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
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
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Human Genetics (IHG)
Institute of Genetic Epidemiology (IGE)
Grants NCI NIH HHS