Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Dec;127(12):2220-2226.
doi: 10.1038/s41416-022-01977-2. Epub 2022 Oct 11.

Adverse prognostic impact of the loss of STAG2 protein expression in patients with newly diagnosed localised Ewing sarcoma: A report from the Children's Oncology Group

David S Shulman  1 , Sonja Chen  2 , David Hall  3 , Anwesha Nag  4 , Aaron R Thorner  4 , Stephen L Lessnick  2 , Kimberly Stegmaier  1 , Katherine A Janeway  1 , Steven G DuBois  1 , Mark D Krailo  3   5 , Donald A Barkauskas  3   5 , Alanna J Church  6 , Brian D Crompton  7   8
Affiliations

Adverse prognostic impact of the loss of STAG2 protein expression in patients with newly diagnosed localised Ewing sarcoma: A report from the Children's Oncology Group

David S Shulman et al. Br J Cancer. 2022 Dec.

Abstract

Background: Ewing sarcoma (EWS) is an aggressive sarcoma with no validated molecular biomarkers. We aimed to determine the frequency of STAG2 protein loss by immunohistochemistry (IHC) and whether loss of expression is associated with outcome.

Methods: We performed a retrospective cohort study of patients with EWS enrolled to Children's Oncology Group studies. We obtained unstained slides from 235 patients and DNA for sequencing from 75 patients. STAG2 expression was tested for association with clinical features and survival was estimated using Kaplan-Meier methods with log-rank tests.

Results: In total, 155 cases passed quality control for STAG2 IHC. STAG2 expression in 20/155 cases could not be categorised with the limited available tissue, leaving 135 patients with definitive STAG2 IHC. In localised and metastatic disease, STAG2 was lost in 29/108 and 6/27 cases, respectively. Among patients with IHC and sequencing, 0/17 STAG2 expressing cases had STAG2 mutations, and 2/7 cases with STAG2 loss had STAG2 mutations. Among patients with localised disease, 5-year event-free survival was 54% (95% CI 34-70%) and 75% (95% CI 63-84%) for patients with STAG2 loss vs. expression (P = 0.0034).

Conclusion: STAG2 loss of expression is identified in a population of patients without identifiable STAG2 mutations and carries a poor prognosis.

PubMed Disclaimer

Conflict of interest statement

DSS has received fees for consulting from Boehringer Ingelheim. KAJ has received fees for consulting, travel support or honoraria for speaking from Bayer, Roche, Foundation Medicine and Ipsen. SGD has received fees for consulting and advisory board roles from Amgen, Bayer and Jazz Pharmaceuticals and has received travel expenses from Loxo Oncology, Roche, and Salarius. KS receives grant funding as part of the DFCI/Novartis Drug Discovery Program and from Kronos Bio, is a SAB member with stock options with Auron Therapeutics, and has previously consulted for AstraZeneca. AJC has received consulting fees from Bayer. BDC has received funding for unrelated experiments from Gradalis, and his spouse was previously employed and received equity from Acceleron Pharma.

Figures

Fig. 1
Fig. 1. Study schema.
Overview of the study schema for patients with material for STAG2 staining and for whole-genome-amplified sequencing.
Fig. 2
Fig. 2. Survival stratified by STAG2 expression.
Event-free survival (EFS) (a) and overall survival (OS) (b) for patients with localised Ewing sarcoma, and EFS (c) and OS (d) for patients with metastatic Ewing sarcoma stratified by STAG2 expression (STAG2 lost in blue; STAG2 expressed in red dashed).
Fig. 3
Fig. 3. Cumulative incidence of relapse stratified by STAG2 expression.
Cumulative incidence of the event by STAG2 IHC status for distant only relapse (a; n = 14), local only relapse (b; n = 5), and combined local and distant relapse (c; n = 9; STAG2 lost in blue; STAG2 expressed in red dashed).
See this image and copyright information in PMC

References

    1. Tirode F, Surdez D, Ma X, Parker M, Le Deley MC, Bahrami A, et al. Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov. 2014;4:1342–53. doi: 10.1158/2159-8290.CD-14-0622. - DOI - PMC - PubMed
    1. Crompton BD, Stewart C, Taylor-Weiner A, Alexe G, Kurek KC, Calicchio ML, et al. The genomic landscape of pediatric Ewing sarcoma. Cancer Discov. 2014;4:1326–41. doi: 10.1158/2159-8290.CD-13-1037. - DOI - PubMed
    1. Brohl AS, Solomon DA, Chang W, Wang J, Song Y, Sindiri S, et al. The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet. 2014;10:e1004475. doi: 10.1371/journal.pgen.1004475. - DOI - PMC - PubMed
    1. Leavey PJ, Laack NN, Krailo MD, Buxton A, Randall RL, DuBois SG, et al. Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children’s Oncology Group Report. J Clin Oncol. 2021;39:4029–38. doi: 10.1200/JCO.21.00358. - DOI - PMC - PubMed
    1. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N. Engl J Med. 2003;348:694–701. doi: 10.1056/NEJMoa020890. - DOI - PubMed