European genetic ancestry associated with risk of childhood ependymoma

Chenan Zhang; Quinn T Ostrom; Helen M Hansen; Julio Gonzalez-Maya; Donglei Hu; Elad Ziv; Libby Morimoto; Adam J de Smith; Ivo S Muskens; Cassie N Kline; Zalman Vaksman; Hakon Hakonarson; Sharon J Diskin; Carol Kruchko; Jill S Barnholtz-Sloan; Vijay Ramaswamy; Francis Ali-Osman; Melissa L Bondy; Michael D Taylor; Catherine Metayer; Joseph L Wiemels; Kyle M Walsh

doi:10.1093/neuonc/noaa130

European genetic ancestry associated with risk of childhood ependymoma

Neuro Oncol. 2020 Nov 26;22(11):1637-1646. doi: 10.1093/neuonc/noaa130.

Authors

Chenan Zhang¹, Quinn T Ostrom^{2

3}, Helen M Hansen⁴, Julio Gonzalez-Maya⁴, Donglei Hu⁵, Elad Ziv⁵, Libby Morimoto⁶, Adam J de Smith⁷, Ivo S Muskens⁷, Cassie N Kline^{8

9}, Zalman Vaksman¹⁰, Hakon Hakonarson^{11

12}, Sharon J Diskin^{10

12}, Carol Kruchko⁹, Jill S Barnholtz-Sloan¹³, Vijay Ramaswamy¹⁴, Francis Ali-Osman¹⁵, Melissa L Bondy², Michael D Taylor¹⁴, Catherine Metayer⁶, Joseph L Wiemels⁷, Kyle M Walsh^{1

15}

Affiliations

¹ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
² Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
³ Central Brain Tumor Registry of the United States, Hinsdale, Illinois, USA.
⁴ Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
⁵ Division of General Internal Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
⁶ School of Public Health, University of California Berkeley Berkeley, California, USA.
⁷ Center for Genetic Epidemiology, University of Southern California, Los Angeles, California, USA.
⁸ Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.
⁹ Department of Neurology, University of California San Francisco, San Francisco, California, USA.
¹⁰ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹¹ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹² Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹³ Department of Population and Quantitative Health Sciences and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
¹⁴ The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁵ Department of Neurosurgery and Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina, USA.

Abstract

Background: Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations.

Methods: In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS).

Results: CBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08-1.59, Pmeta = 6.7 × 10-3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45-2.73; P = 2.2 × 10-5) but which was not validated in an independent set of posterior fossa type A patients.

Conclusions: Interethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.

Keywords: disparities; ependymoma; ethnicity; genetic ancestry; pediatric cancer; race.

Publication types

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

MeSH terms

Black or African American
Child
Ependymoma* / epidemiology
Ependymoma* / genetics
Female
Hispanic or Latino
Humans
Male
United States
White People / genetics

Supplementary concepts

Familial ependymoma

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding