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

Lee OW, Rodrigues C, Lin SH, Luo W, Jones K, Brown DW, Zhou W, Karlins E, Khan SM, Baulande S, Raynal V, Surdez D, Reynaud S, Rubio RA, Zaidi S, Grossetête S, Ballet S, Lapouble E, Laurence V, Pierron G, Gaspar N, Corradini N, Marec-Bérard P, Rothman N, Dagnall CL, Burdett L, Manning M, Wyatt K, Yeager M, Chari R, Leisenring WM, Kulozik AE, Kriebel J, Meitinger T, Strauch K, Kirchner T, Dirksen U, Mirabello L, Tucker MA, Tirode F, Armstrong GT, Bhatia S, Robison LL, Yasui Y, Romero-Pérez L, Hartmann W, Metzler M, Diver WR, Lori A, Freedman ND, Hoover RN, Morton LM, Chanock SJ, Grünewald TG, Delattre O, Machiela MJ (2023)

Publication Type: Journal article

Publication year: 2023

Journal

American Journal of Human Genetics Elsevier (Cell Press)

Book Volume: 110

Pages Range: 427-441

Journal Issue: 3

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.

Authors with CRIS profile

Markus Metzler Professur für Kinder- und Jugendmedizin mit dem Schwerpunkt Pädiatrische Onkologie und Hämatologie

Involved external institutions

National Cancer Institute (NCI) US United States (USA) (US) Institut Curie FR France (FR) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Institut Gustave-Roussy FR France (FR) Université de Lyon (UDL) FR France (FR) Fred Hutchinson Cancer Research Center CA Canada (CA) Universitätsklinikum Heidelberg DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Universitätsklinikum Essen DE Germany (DE) St. Jude Children’s Research Hospital US United States (USA) (US) University of Alabama at Birmingham (UAB) US United States (USA) (US) Universitätsklinikum Münster DE Germany (DE) American Cancer Society US United States (USA) (US)

How to cite

APA:

Lee, O.W., Rodrigues, C., Lin, S.H., Luo, W., Jones, K., Brown, D.W.,... Machiela, M.J. (2023). Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding. American Journal of Human Genetics, 110(3), 427-441. https://doi.org/10.1016/j.ajhg.2023.01.017

MLA:

Lee, Olivia W., et al. "Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding." American Journal of Human Genetics 110.3 (2023): 427-441.

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