Journal Article

DKFZ-2023-00351

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding.

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. ; Grossetête, 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.DKFZ* ; Kriebel, J. ; Meitinger, T. ; Strauch, K. ; Kirchner, T.DKFZ* ; Dirksen, U. ; Mirabello, L. ; Tucker, M. A. ; Tirode, F. ; Armstrong, G. T. ; Bhatia, S. ; Robison, L. L. ; Yasui, Y. ; Romero-Pérez, L.DKFZ* ; Hartmann, W. ; Metzler, M. ; Diver, W. R. ; Lori, A. ; Freedman, N. D. ; Hoover, R. N. ; Morton, L. M. ; Chanock, S. J. ; Grünewald, T.DKFZ* ; Delattre, O. ; Machiela, M. J.

2023
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.ajhg.2023.01.017

Abstract: 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.

Keyword(s): 6p25.1 ; EWSR1-FLI1 ; Ewing sarcoma ; GGAA microsatellite ; GWAS ; RREB1 ; germline somatic interaction ; long-read sequencing

Note: 2023 Mar 2;110(3):427-441

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Contributing Institute(s):

1. Translationale Pädiatrische Sarkomforschung (B410)
2. DKTK HD zentral (HD01)
3. KKE Pädiatrische Leukämie (A400)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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