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Paper Spotlight: Germline predisposition to pediatric Ewing sarcoma

This blog is part of our Paper Spotlight series, which features peer-reviewed research publications involving work done in Terra and highlights how the analysis methods were applied.


Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes

By Riaz Gillani, Sabrina Y. Camp, Seunghun Han, Jill K. Jones, Hoyin Chu, Schuyler O’Brien, Erin L. Young, Lucy Hayes, Gareth Mitchell, Trent Fowler, Alexander Gusev, Junne Kamihara, Katherine A. Janeway, Joshua D. Schiffman, Brian D. Crompton, Saud H. AlDubayan and Eliezer M. Van Allen

The American Journal of Human Genetics (2022) https://doi.org/10.1016/j.ajhg.2022.04.007

Abstract: More knowledge is needed regarding germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. Here, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out European-focused and pan-ancestry case-control analyses to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1,147 individuals with pediatric sarcoma diagnoses (226 Ewing sarcoma, 438 osteosarcoma, 180 rhabdomyosarcoma, and 303 other sarcoma) relative to identically processed cancer-free control individuals. Findings in Ewing sarcoma were validated with an additional cohort of 430 individuals, and a subset of 301 Ewing sarcoma parent-proband trios was analyzed for inheritance patterns of identified pathogenic variants. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma relative to other sarcoma subtypes. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the European Ewing sarcoma discovery cohort (three individuals, OR 12.6, 95% CI 3.0–43.2, p = 0.003, FDR = 0.40). This enrichment in FANCC heterozygous pathogenic variants was again observed in the European Ewing sarcoma validation cohort (three individuals, OR 7.0, 95% CI 1.7–23.6, p = 0.014), representing a broader importance of genes involved in DNA damage repair, which were also nominally enriched in individuals with Ewing sarcoma. Pathogenic variants in DNA damage repair genes were acquired through autosomal inheritance. Our study provides new insight into germline risk factors contributing to Ewing sarcoma pathogenesis.


What part of the work was done in Terra?

Excerpts from the paper’s Methods section:

Raw sequencing data was downloaded to Terra (https://firecloud.terra.bio/), a collaborative cloud-computing platform utilized for genomic analyses, developed as part of the NCI Cloud Pilot program and supported by the Broad Institute.

Personal communication from first author Riaz Gillani:

We used Terra for many parts of the analysis, including harmonizing raw sequencing data, calling variants, inferring ancestry, running quality control, and counting variants. Some of the key public workflows that enabled this were DeepVariant, BAMRealigner, and various adaptations of the GATK workflows.

Links to the relevant public workflows:




How did they do it?

Automated workflows 

The authors used previously described bioinformatics analysis pipelines implemented as WDL workflows and shared in the Broad Methods Repository

Terra also supports importing workflows from Dockstore, a free and open source platform for sharing reusable and scalable analytical tools and workflows. 

They ran the workflows at scale using Terra’s workflow execution service

To try your hand at running a workflow in Terra, check out the Workflows Quickstart Guide

Interactive analysis

The authors used Jupyter Notebooks in Terra’s interactive Cloud Environments system for the ancestry inference analysis. 

To get started with Jupyter Notebooks in Terra, check out the Notebooks Quickstart Guide.




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