Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Lin, Shu-Hong; Sampson, Joshua N.; Grünewald, Thomas G.P.; Surdez, Didier; Reynaud, Stéphanie; Mirabeau, Olivier; Karlins, Eric; Rubío, Rebeca Alba; Zaïdi, Sakina; Grossetête-Lalami, Sandrine; Ballet, Steven; Lapouble, Eve; Laurence, Valérie; Michon, Jean; Kovar, Heinrich; Kontny, Udo; González‐Neira, Anna; Alonso, Javier; Corradini, Nadège; Bérard, P; Miller, Jeremy S.; Freedman, Neal D.; Rothman, Nathaniel; Carter, Brian D.; Dagnall, Casey; Burdett, Laurie; Jones, Kristine; Manning, Michelle; Wyatt, Kathleen; Zhou, Weiyin; Yeager, Meredith; Cox, David G.; Hoover, Robert N.; Khan, Javed; Armstrong, Gregory T.; Leisenring, Wendy M.; Bhatia, Smita; Robison, Leslie L.; Kulozik, Andreas E.; Kriebel, Jennifer; Meitinger, Thomas; Metzler, Markus; Krumbholz, Manuela; Hartmann, Wolfgang; Strauch, Konstantin; Kirchner, Thomas; Dirksen, Uta; Mirabello, Lisa; Tucker, Margaret A.; Tirode, Franck; Morton, Lindsay M.; Chanock, Stephen J.; Delattre, Olivier; Machiela, Mitchell J.

doi:10.1371/journal.pone.0237792

Cited by 10 publications

(5 citation statements)

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“…However, it remains unclear whether these factors contribute to incidence trends that we observed in older age groups, and few other extrinsic factors have been associated with this disease 9,26,27,31 . More recent analyses indicate that germline genetic susceptibility contributes substantially to ES development and may be a stronger risk factor than locally varying extrinsic factors 32‐34 . However, changes to the frequency of genetic risk variants within a population are unlikely to have occurred during a 25‐year timespan.…”

Section: Discussionmentioning

confidence: 86%

“…9,26,27,31 More recent analyses indicate that germline genetic susceptibility contributes substantially to ES development and may be a stronger risk factor than locally varying extrinsic factors. [32][33][34] However, changes to the frequency of genetic risk variants within a population are unlikely to have occurred during a 25-year timespan. Therefore, the possibility that at least some of the trends we observed in ES incidence are a consequence of changing case detection and recognition over time merits consideration.…”

Section: Discussionmentioning

confidence: 99%

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Comparative international incidence of Ewing sarcoma 1988 to 2012

Spector

Hubbard

Diessner

et al. 2021

Intl Journal of Cancer

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Ewing sarcoma (ES) is the second most common primary bone tumor in children and adolescents. There are few known epidemiological or genetic risk factors for ES. Numerous reports describe incidence rates and trends within the United States, but international comparisons are sparse. We used the Cancer Incidence in Five Continents (CI5) data to estimate age standardized incidence rates (ASRs; cases per million) and 95% confidence intervals (95% CIs), male-to-female incidence rate ratios (IRRs; 95% CI), and the average annual percent change in incidence (AAPC; 95% CI) for ES by geographic region for children and adults aged 0 to 49 years. We also estimated the ASR for each country or country subpopulation among the 10-to 19-year-old age range; capturing the peak incidence of ES. In total, 15 874 ES cases ages 0 to 49 were reported in the CI5 series between 1988 and 2012. AAPC estimates varied by age group and geographic region. Most of the statistically significant AAPCs showed an increased incidence over time; the only statistically significant decreases in incidence were observed among 20-to 29-year-olds and 30-to 39-year-olds in Southern Asia at À1.93% and À1.67%. When categorized by predominant ancestry, we observed countries and subpopulations with predominately African, East Asian, and Southeast Asian ancestry had the lowest incidence rates, whereas Pacific Islanders and populations with predominantly European and North African/Middle Eastern ancestry had the highest. An excess incidence in males was observed in most regions. Our results highlight substantial variation in ES incidence across geographic populations, reflecting potential ancestral influence on disease risk.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Comparative international incidence of Ewing sarcoma 1988 to 2012

Spector

Hubbard

Diessner

et al. 2021

Intl Journal of Cancer

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“…Understanding the pathogenesis of ES is essential for identifying new biomarkers to develop new therapeutic strategies [12,13]. However, metastasis and recurrence are the main causes of poor prognosis of ES [14,15].…”

Section: Discussionmentioning

confidence: 99%

Weighted Gene Co-Expression Network Analysis Reveals a New Survival Model for Prognostic Prediction in Ewing Sarcoma

Li¹,

Wang²,

Wang³

et al. 2021

Preprint

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Background: Ewing sarcoma (ES) is a malignant bone or soft-tissue cancer that mainly arises in children and young adults. However, the prognosis of Ewing sarcoma remains very poor, and there is no effective prediction method. The aim of our study was to identify a prognostic model for ES patients based on prognosis-associated mRNA expression profiles. Methods: The GSE17679 dataset was downloaded from the Gene Expression Omnibus (GEO) database. Differently expressed genes (DEGs) between ES and normal control were identified using R package “limma”. A weighted gene co-expression network analysis (WGCNA) was used to screen gene modules associated with recurrence/metastasis and survival status based on DEGs. Results: The prognostic model was constructed based on genes in MEbrown module, which was most associated with recurrence/metastasis and survival status, using Kaplan-Meier survival and lasso regression analysis. Sixteen genes were screened to construct the prognostic model. ES patients were grouped into high- and low-risk groups based on the median of risk score calculated for each of them. ES patients in high-risk group have worse survival than patients in low-risk group. The AUCs (Area under the ROC curve) for 1-year, 3-year, and 6-year overall survival were 0.903, 0.995, 0.953. Conclusions: Taken together, our research constructed a prognostic model which has excellent prediction performance for overall survival of ES patients.

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“…In one study, first-degree relatives of patients with EwS have an increased risk of developing cancers such as brain and female genital cancers, and second-degree relatives demonstrated an increased risk of breast cancer among others 102 . Genome-wide association studies have identified genetic haplotypes associated with an increased risk of EwS 103 , 104 , which possibly contribute to disease onset through generating higher affinity binding sites for EWSR1::FLI1 as shown at EGR2 cis-regulatory elements 105 , 106 .…”

Section: Summary Of Evidence For Molecular Biomarkers For Risk-strati...mentioning

confidence: 99%

An international working group consensus report for the prioritization of molecular biomarkers for Ewing sarcoma

et al. 2022

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The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60–80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment.

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Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Abstract: Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here:

Cited by 10 publications

References 36 publications

Comparative international incidence of Ewing sarcoma 1988 to 2012

Comparative international incidence of Ewing sarcoma 1988 to 2012

Weighted Gene Co-Expression Network Analysis Reveals a New Survival Model for Prognostic Prediction in Ewing Sarcoma

An international working group consensus report for the prioritization of molecular biomarkers for Ewing sarcoma

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