European genetic ancestry associated with risk of childhood ependymoma

Author:

Zhang Chenan1,Ostrom Quinn T23ORCID,Hansen Helen M4,Gonzalez-Maya Julio4,Hu Donglei5ORCID,Ziv Elad5ORCID,Morimoto Libby6ORCID,de Smith Adam J7,Muskens Ivo S7,Kline Cassie N89,Vaksman Zalman10ORCID,Hakonarson Hakon1112ORCID,Diskin Sharon J1012ORCID,Kruchko Carol9,Barnholtz-Sloan Jill S13ORCID,Ramaswamy Vijay14ORCID,Ali-Osman Francis15,Bondy Melissa L2,Taylor Michael D14,Metayer Catherine6,Wiemels Joseph L7,Walsh Kyle M115

Affiliation:

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

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.

Funder

Pediatric Brain Tumor Foundation

Sontag Foundation

National Cancer Institute

National Institutes of Health

Cancer Prevention and Research Institute of Texas

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Clinical Neurology,Oncology

Reference43 articles.

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3. Clinical presentation, immunohistochemistry and electron microscopy indicate neurofibromatosis type 2-associated gliomas to be spinal ependymomas;Hagel;Neuropathology.,2012

4. Analysis of the neurofibromatosis 2 gene in human ependymomas and astrocytomas;Rubio;Cancer Res.,1994

5. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies;Ruggieri;Acta Otorhinolaryngol Ital.,2016

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