A genome-wide association study on medulloblastoma

Anna M Dahlin; Carl Wibom; Ulrika Andersson; Jonas Bybjerg-Grauholm; Isabelle Deltour; David M Hougaard; Michael E Scheurer; Ching C Lau; Roberta McKean-Cowdin; Rebekah J Kennedy; Long T Hung; Janis Yee; Ashley S Margol; Jessica Barrington-Trimis; W James Gauderman; Maria Feychting; Joachim Schüz; Martin Röösli; Kristina Kjaerheim; Cefalo Study Group; Danuta Januszkiewicz-Lewandowska; Marta Fichna; Jerzy Nowak; Susan Searles Nielsen; Shahab Asgharzadeh; Lisa Mirabello; Ulf Hjalmars; Beatrice Melin

doi:10.1007/s11060-020-03424-9

A genome-wide association study on medulloblastoma

J Neurooncol. 2020 Apr;147(2):309-315. doi: 10.1007/s11060-020-03424-9. Epub 2020 Feb 13.

Authors

Anna M Dahlin¹, Carl Wibom¹, Ulrika Andersson¹, Jonas Bybjerg-Grauholm², Isabelle Deltour^{3

4}, David M Hougaard², Michael E Scheurer⁵, Ching C Lau⁵, Roberta McKean-Cowdin⁶, Rebekah J Kennedy⁷, Long T Hung⁸, Janis Yee⁸, Ashley S Margol⁸, Jessica Barrington-Trimis⁶, W James Gauderman⁶, Maria Feychting⁹, Joachim Schüz³, Martin Röösli^{10

11}, Kristina Kjaerheim¹²; Cefalo Study Group; Danuta Januszkiewicz-Lewandowska^{13

14}, Marta Fichna¹⁵, Jerzy Nowak¹³, Susan Searles Nielsen^{16

17}, Shahab Asgharzadeh^{8

18}, Lisa Mirabello¹⁹, Ulf Hjalmars¹, Beatrice Melin²⁰

Collaborators

Cefalo Study Group:
Michaela Prochazka, Maral Adel Fahmideh, Birgitta Lannering, Lisbeth S Schmidt, Christoffer Johansen, Astrid Sehested, Claudia Kuehni, Michael Grotzer, Tore Tynes, Tone Eggen, Lars Klæboe

Affiliations

¹ Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
² Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
³ Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, France.
⁴ Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark.
⁵ Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁸ Department of Pediatrics, Section of Hematology-Oncology, Children's Hospital Los Angeles and The Saban Research Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
⁹ Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.
¹¹ University of Basel, Basel, Switzerland.
¹² The Cancer Registry of Norway, Oslo, Norway.
¹³ Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
¹⁴ Department of Pediatric Oncology, Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.
¹⁵ Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland.
¹⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁷ Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA.
¹⁸ Department of Pathology, Saban Research Institute at Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
²⁰ Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden. beatrice.melin@umu.se.

Abstract

Introduction: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark.

Methods: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2.

Results: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10^-5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10^-8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (OR_T = 1.59, p_validation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, OR_T = 3.76, p = 3.2 × 10^-4) and rs79036813 (PTCH1, OR_A = 0.42, p = 2.6 × 10^-3).

Conclusion: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.

Keywords: Adolescents and young adults (AYA); CNS cancers; Epidemiology; Genetics of risk, outcome, and prevention; Pediatric cancers.

MeSH terms

Biomarkers, Tumor / genetics*
Case-Control Studies
Cerebellar Neoplasms / genetics*
Cerebellar Neoplasms / pathology
Cohort Studies
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Genotype
Humans
Medulloblastoma / genetics*
Medulloblastoma / pathology
Polymorphism, Single Nucleotide*
Prognosis

Substances

Biomarkers, Tumor

Abstract

MeSH terms

Substances

Grants and funding