Review: Ewing Sarcoma Predisposition
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REVIEW
Review: Ewing Sarcoma Predisposition Pablo Gargallo 1 & Yania Yáñez 1 & Antonio Juan 2 & Vanessa Segura 1 & Julia Balaguer 2 & Bárbara Torres 2 & Silves Oltra 3,4 & Victoria Castel 2 & Adela Cañete 2 Received: 28 June 2019 / Accepted: 10 October 2019 # Arányi Lajos Foundation 2019
Abstract Ewing sarcoma is a rare tumor developed in bone and soft tissues of children and teenagers. This entity is biologically led by a chromosomal translocation, typically including EWS and FLI1 genes. Little is known about Ewing sarcoma predisposition, although the role of environmental factors, ethnicity and certain polymorphisms on Ewing sarcoma susceptibility has been studied during the last few years. Its prevalence among cancer predisposition syndromes has also been thoroughly examined. This review summarizes the available evidence on predisposing factors involved in Ewing sarcoma susceptibility. On the basis of these data, an integrated approach of the most influential factors on Ewing sarcoma predisposition is proposed. Keywords Ewing sarcoma . Cancer predisposition . Genetic susceptibility . Polymorphism
Abbreviations ES Ewing sarcoma CNV Copy number variations CPS Cancer predisposing syndromes MSC Mesenchymal Stem Cell AACR American Association of Cancer Research LFS Li-Fraumeni Syndrome WGS whole genome sequencing WES Whole exome sequencing NGS Next generation sequencing RB1 RB transcriptional corepressor 1 BLM Bloom Syndrome RecQ Like Helicase gene; Bloom syndrome gene RET RET Proto-Oncogene GENESIS Genetics of Ewing Sarcoma International study
* Pablo Gargallo [email protected] 1
Clinical and Translational Oncology Research Group, La Fe Hospital, Av. Fernando Abril Martorell 106 Postal Code, 46026 Valencia, Spain
2
Pediatric Oncology and Hematology Unit, La Fe Hospital, Valencia, Spain
3
Genetics Unit, La Fe Hospital, Valencia, Spain
4
Genetics Department, Valencia University, Valencia, Spain
Introduction Ewing sarcoma (ES) is an aggressive and rare tumor developed usually in bone, but sometimes in soft tissues as well [1], whose incidence is estimated to be 1.2 cases/million in U.S. [2]. White people have higher incidence than black and Asian people [3, 4], and there is a peak between 5 and 24 years old [1, 5–13]. Chromosomal translocation between TET and ETS genes is the best known and the most important molecular event in ES. Most of cases present a balanced reciprocal chromosomal translocation (t(11;22)(q24;q12)), which results in EWS/FLI1 oncogenic gene fusion [14]. Fusion protein EWS/FLI1 acts as a pathogenic transcription factor and determines tumor development [15–22]. The chromatin remodeling event mediated by EWS/FLI1 leads to gene activation and repression [22]. GGAA microsatellite regions are the binding site of EWS/ FLI1 [23–27]. The oncogenic transcription program mediated by EWS/FLI, up-regulates and down-regulates thousands of genes [15, 16]. Some copy number variations (CNV) (gain of chromosome 1q, 8, 12 and loss of 9p21 and 16q) [28–30] and gene mutations (in STAG2, TP53 and Rb1gen
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