Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding
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...
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2 March 2023
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| In: |
The American journal of human genetics
Year: 2023, Jahrgang: 110, Heft: 3, Pages: 427-441 |
| ISSN: | 1537-6605 |
| DOI: | 10.1016/j.ajhg.2023.01.017 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ajhg.2023.01.017 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0002929723000174 
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| Verfasserangaben: | Olivia W. Lee, Calvin Rodrigues, Shu-Hong Lin, Wen Luo, Kristine Jones, Derek W. Brown, Weiyin Zhou, Eric Karlins, Sairah M. Khan, Sylvain Baulande, Virginie Raynal, Didier Surdez, Stephanie Reynaud, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetête, Stelly Ballet, Eve Lapouble, Valérie Laurence, Gaelle Pierron, Nathalie Gaspar, Nadège Corradini, Perrine Marec-Bérard, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdett, Michelle Manning, Kathleen Wyatt, Meredith Yeager, Raj Chari, Wendy M. Leisenring, Andreas E. Kulozik, Jennifer Kriebel, Thomas Meitinger, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Gregory T. Armstrong, Smita Bhatia, Leslie L. Robison, Yutaka Yasui, Laura Romero-Pérez, Wolfgang Hartmann, Markus Metzler, W. Ryan Diver, Adriana Lori, Neal D. Freedman, Robert N. Hoover, Lindsay M. Morton, Stephen J. Chanock, Thomas G.P. Grünewald, Olivier Delattre, Mitchell J. Machiela |
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| 245 | 1 | 0 | |a Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding |c Olivia W. Lee, Calvin Rodrigues, Shu-Hong Lin, Wen Luo, Kristine Jones, Derek W. Brown, Weiyin Zhou, Eric Karlins, Sairah M. Khan, Sylvain Baulande, Virginie Raynal, Didier Surdez, Stephanie Reynaud, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetête, Stelly Ballet, Eve Lapouble, Valérie Laurence, Gaelle Pierron, Nathalie Gaspar, Nadège Corradini, Perrine Marec-Bérard, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdett, Michelle Manning, Kathleen Wyatt, Meredith Yeager, Raj Chari, Wendy M. Leisenring, Andreas E. Kulozik, Jennifer Kriebel, Thomas Meitinger, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Gregory T. Armstrong, Smita Bhatia, Leslie L. Robison, Yutaka Yasui, Laura Romero-Pérez, Wolfgang Hartmann, Markus Metzler, W. Ryan Diver, Adriana Lori, Neal D. Freedman, Robert N. Hoover, Lindsay M. Morton, Stephen J. Chanock, Thomas G.P. Grünewald, Olivier Delattre, Mitchell J. Machiela |
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| 520 | |a 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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| 650 | 4 | |a GGAA microsatellite | |
| 650 | 4 | |a GWAS | |
| 650 | 4 | |a long-read sequencing | |
| 650 | 4 | |a RREB1 | |
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