Mutational landscape of primary and recurrent Ewing sarcoma

Paulina Jagodzińska-Mucha; Paweł Sobczuk; Michał Mikuła; Anna Raciborska; Anna Dawidowska; Maria Kulecka; Katarzyna Bilska; Anna Szumera-Ciećkiewicz; Anna Kluska; Magdalena Piątkowska; Anna Bałabas; Piotr Rutkowski; Iwona Ługowska

doi:10.5114/wo.2021.112234

eISSN: 1897-4309
ISSN: 1428-2526

Contemporary Oncology/Współczesna Onkologia

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4/2021
vol. 25

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abstract:

Original paper

Mutational landscape of primary and recurrent Ewing sarcoma

Paulina Jagodzińska-Mucha

¹

,

Paweł Sobczuk

^{1, 2}

,

Michał Mikuła

³

,

Anna Raciborska

⁴

,

Anna Dawidowska

⁵

,

Maria Kulecka

^{3, 6}

,

Katarzyna Bilska

⁴

,

Anna Szumera-Ciećkiewicz

^{7, 8}

,

Anna Kluska

³

,

Magdalena Piątkowska

³

,

Anna Bałabas

³

,

Piotr Rutkowski

¹

,

Iwona Ługowska

^{1, 5}

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
Department of Experimental and Clinical Physiology, Laboratory of Centre of Preclinical Research, Medical University of Warsaw, Warsaw, Poland
Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
Department of Oncology and Surgical Oncology for Children and Youth, Mother and Child Institute, Warsaw, Poland
Early Phase Clinical Trials Unit, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
Department of Gastroenterology, Hepatology and Clinical Oncology, Centre for Postgraduate Medical Education, Warsaw, Poland
Department of Pathology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
Diagnostic Hematology Department, Institute of Hematology and Transfusion Medicine, Warsaw, Poland

Contemp Oncol (Pozn) 2021; 25 (4): 241–248

DOI: https://doi.org/10.5114/wo.2021.112234

Online publish date: 2021/12/29

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Introduction
Ewing sarcoma (ES) is a highly aggressive malignancy of bone and soft tissues characterized by the presence of a genetic fusion involving the EWSR1 gene. More than one-third of patients develop distant metastases, which are associated with unfavorable prognosis. Knowledge about the disease’s genetic landscape may help foster progress in using targeted therapies in the treatment of ES.

Aim of the study
The objective is to assess the mutational landscape of ES in pretreatment samples, tumor samples after neoadjuvant chemotherapy, and in metastatic/recurrent tumors in children and adults.

Material and methods
DNA from 39 formalin-fixed paraffin-embedded tumor samples of 22 patients (17 adults, 5 children) were analyzed by targeted next generation sequencing (NGS) using the Oncomine Comprehensive Assay v3gene panel. Additional functional analyses were performed between patient subgroups.

Results
All samples were characterized by low tumor mutation burden (< 10 mut/Mb). The most commonly mutated genes were PIK3R1 (59%) and POLE (50%). The most widely detected variants in biopsy samples were PIK3R1 T369I (50%), FGFR1 E159K, and TP53 at codon 72 (both in 27.3%). Additionally, the ATR, BRCA1, RAD50, ATM, CHEK1, and NBN genes showed a significantly higher number of mutations in ES. Mutations in PIK3R1 were significantly more frequent in adults, while mutations in the pathways responsible for cell cycle control, DNA repair, and transcriptional regulation were more frequent in children.

Conclusions
Besides EWSR1 fusion, ES is characterized by numerous point mutations that are potential targets for precision medicine. There is high genomic heterogeneity that may explain differences in outcomes between patient subgroups.

keywords:

Mutational landscape of primary and recurrent Ewing sarcoma

Paulina Jagodzińska-Mucha 1 , Paweł Sobczuk 1, 2 , Michał Mikuła 3 , Anna Raciborska 4 , Anna Dawidowska 5 , Maria Kulecka 3, 6 , Katarzyna Bilska 4 , Anna Szumera-Ciećkiewicz 7, 8 , Anna Kluska 3 , Magdalena Piątkowska 3 , Anna Bałabas 3 , Piotr Rutkowski 1 , Iwona Ługowska 1, 5

genetics, mutation, NGS, targeted therapies, Ewing sarcoma