A genome-wide association study on medulloblastoma.
Dahlin AMDepartment of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
Wibom CDepartment of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
Andersson UDepartment of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
Bybjerg-Grauholm JDanish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Deltour ISection of Environment and Radiation, International Agency for Research on Cancer, Lyon, France.
Hougaard DMDanish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Scheurer MEDepartment of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Lau CCDepartment of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
McKean-Cowdin RDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Kennedy RJChildren's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Hung LTDepartment 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.
Yee JDepartment 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.
Margol ASDepartment 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.
Barrington-Trimis JDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Gauderman WJDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Feychting MUnit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Schüz JSection of Environment and Radiation, International Agency for Research on Cancer, Lyon, France.
Röösli MDepartment of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.
Kjaerheim KThe Cancer Registry of Norway, Oslo, Norway.
Januszkiewicz-Lewandowska DDepartment of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland.
Fichna MInstitute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
Nowak JPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Searles Nielsen SDepartment 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.
Asgharzadeh SDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Mirabello LDepartment of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
English
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 (ORT = 1.59, pvalidation = 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, ORT = 3.76, p = 3.2 × 10-4) and rs79036813 (PTCH1, ORA = 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.