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

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; Eliezer M Van Allen

doi:10.1016/j.ajhg.2022.04.007

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

Am J Hum Genet. 2022 Jun 2;109(6):1026-1037. doi: 10.1016/j.ajhg.2022.04.007. Epub 2022 May 4.

Authors

Riaz Gillani¹, Sabrina Y Camp², Seunghun Han³, Jill K Jones⁴, Hoyin Chu², Schuyler O'Brien⁵, Erin L Young⁵, Lucy Hayes⁵, Gareth Mitchell⁵, Trent Fowler⁵, Alexander Gusev⁶, Junne Kamihara⁷, Katherine A Janeway¹, Joshua D Schiffman⁸, Brian D Crompton¹, Saud H AlDubayan⁹, Eliezer M Van Allen¹⁰

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA; Boston Children's Hospital, Boston, MA 02115, USA.
² Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA.
³ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA.
⁴ Harvard Medical School, Boston, MA 02115, USA.
⁵ Huntsman Cancer Institute, 2000 Circle of Hope Dr, Room 4246, Salt Lake City, UT 84112, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115 MA, USA.
⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA; Boston Children's Hospital, Boston, MA 02115, USA.
⁸ Huntsman Cancer Institute, 2000 Circle of Hope Dr, Room 4246, Salt Lake City, UT 84112, USA; Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Peel Therapeutics, Inc., Salt Lake City, UT 84108, USA.
⁹ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA; College of Medicine, King Saudi Bin Abdulaziz University for Health Sciences, Riyadh 14611, Saudi Arabia. Electronic address: saud_aldubayan@dfci.harvard.edu.
¹⁰ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: eliezerm_vanallen@dfci.harvard.edu.

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.

Keywords: Ewing sarcoma, cancer predisposition, pediatric oncology, genetic risk.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Child
DNA Damage / genetics
Genetic Predisposition to Disease
Germ Cells
Germ-Line Mutation / genetics
Humans
Sarcoma* / genetics
Sarcoma, Ewing* / genetics

Abstract

Publication types

MeSH terms

Grants and funding