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Insight in glioma susceptibility through an analysis of 6p22.3, 12p13.33-12.1, 17q22-23.2 and 18q23 SNP genotypes in familial and non-familial glioma

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Abstract

The risk of glioma has consistently been shown to be increased twofold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23. To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations. In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (P trend <1.0 × 10−8). The results support the linkage finding that some loci in the 12p13.33-12.1 and 17q12-q21.32 may contribute to gliomagenesis and suggest potential target genes underscoring linkage signals.

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Abbreviations

PBT:

Primary brain tumor

SNP:

Single nucleotide polymorphism

GWA:

Genome-wide association

LD:

Linkage disequilibrium

LOD:

Logarithm (base 10) of odds

OR:

Odds ratio

CI:

95 % confidence interval

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Acknowledgments

This work was supported by National Institutes of Health (5R01 CA119215, 5R01 CA070917 and R01CA52689). Additional support was provided by the American Brain Tumor Association, The National Brain Tumor Society, the Tug McGraw Foundation and the Wellcome Trust who provided funding for the parent GWAS. The authors acknowledge the input of the Gliogene External Advisory Committee. For more information about the Gliogene Consortium, please refer to the following Web site http://www.gliogene.org.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Yanhong Liu, Michael E. Scheurer, Spiridon Tsavachidis, Georgina N. Armstrong & Melissa L. Bondy

  2. Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA

    Ching C. Lau

  3. Division of Cancer Epidemiology and Genetics, Department Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Preetha Rajaraman, Zhaoming Wang, Martha Linet & Stephen Chanock

  4. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sanjay Shete

  5. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Christopher I. Amos

  6. Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK

    Richard S. Houlston & Fay J. Hosking

  7. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA

    Elizabeth B. Claus

  8. Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA

    Elizabeth B. Claus

  9. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Jill Barnholtz-Sloan

  10. The Neurological Institute of Columbia University, New York, NY, USA

    Rose Lai

  11. Cancer Control and Prevention Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA

    Dora Il’yasova & Joellen Schildkraut

  12. Cancer and Radiation Epidemiology Unit, Chaim Sheba Medical Center, Gertner Institute, Tel Hashomer, Israel

    Siegal Sadetzki

  13. Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Siegal Sadetzki

  14. Department of Neurology, Danish Cancer Society, Copenhagen, Denmark

    Christoffer Johansen

  15. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Jonine L. Bernstein & Sara H. Olson

  16. Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA

    Robert B. Jenkins & Daniel LaChance

  17. Evanston Kellogg Cancer Care Center, North Shore University Health System, Evanston, IL, USA

    Nicholas A. Vick

  18. Department of Neurological Surgery, University of California, San Francisco, CA, USA

    Margaret Wrensch

  19. Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL, USA

    Faith Davis & Bridget J. McCarthy

  20. Department of Radiation Sciences Oncology, Umeå University, Umeå, Sweden

    Beatrice S. Melin & Ulrika Andersson

  21. Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    Patricia A. Thompson

Authors
  1. Yanhong Liu
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  2. Beatrice S. Melin
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  3. Preetha Rajaraman
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  4. Zhaoming Wang
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  31. Stephen Chanock
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  32. Melissa L. Bondy
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The Gliogene Consortium

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Correspondence to Melissa L. Bondy.

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Liu, Y., Melin, B.S., Rajaraman, P. et al. Insight in glioma susceptibility through an analysis of 6p22.3, 12p13.33-12.1, 17q22-23.2 and 18q23 SNP genotypes in familial and non-familial glioma. Hum Genet 131, 1507–1517 (2012). https://doi.org/10.1007/s00439-012-1187-x

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