Distinct germ line polymorphisms underlie glioma morphologic heterogeneity

doi:10.1016/j.cancergencyto.2010.10.002

Cancer Genetics

Volume 204, Issue 1, January 2011, Pages 13-18

https://doi.org/10.1016/j.cancergencyto.2010.10.002 Get rights and content

Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports, it was not clear whether the single nucleotide polymorphism associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci and tumor subtype, we genotyped two case-control groups composed of the spectrum of infiltrating glioma subtypes and stratified the analyses by type. We report that specific germ line polymorphisms are associated with different glioma subtypes. CCDC26 (8q24) region polymorphisms are strongly associated with oligodendroglial tumor risk (rs4295627, odds ratio [OR] = 2.05, P = 8.3 × 10⁻¹¹) but not glioblastoma risk. The opposite is true of RTEL (20q13) region polymorphisms, which are significantly associated with glioblastoma (rs2297440, OR = 0.56, P = 4.6 × 10⁻¹⁰) but not oligodendroglial tumor. The SNPs in or near CCDC26 (8q24) are associated with oligodendroglial tumors regardless of combined 1p and 19q deletion status; however, the association is greatest for those with combined deletion (rs4295627, OR = 2.77, P = 2.6 × 10⁻⁹). These observations generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development.

Section snippets

Mayo Clinic case-control study

The Mayo Clinic case group included 582 individuals with glioma newly diagnosed between 2005 and 2009. Cases were identified within 24 hours of diagnosis, except for those who had their initial diagnosis elsewhere, followed by verification at the Mayo Clinic. Pathologic diagnosis was confirmed by review of the primary surgical material for all cases by two Mayo Clinic neuropathologists, C. Giannini and B. Scheithauer, on the basis of surgically resected material. The control group consisted of

Stratification of germ line risk alleles by oligodendroglial components

Of the five chromosomal regions examined, only 8q24 (CCDC26) was significantly associated with oligodendroglioma or oligoastrocytoma (Figure 1 and Supplemental Table 2). All three of the previously reported 8q24 SNPs were highly significant (e.g., for rs4295627, odds ratio [OR] = 2.05, 95% confidence interval = 1.65–2.54, P = 8.3 × 10⁻¹¹). These associations were found in both case-control groups and in tumors with either oligodendroglioma or mixed oligoastrocytoma morphology (Supplemental

Discussion

We show that 8q24 polymorphisms were associated with gliomas containing an oligodendroglial component but not with GBM. Conversely, the 5p15, 9p21, and 20q13 regions were associated with GBM risk but were not strongly associated with oligodendroglial tumors. This pattern supports the current model of glioma initiation and progression. For example, because 8q24 associations are observed for risk of oligodendroglioma regardless of 1p/19q deletion, as well as potentially with non-GBM astrocytoma,

Acknowledgments

The research at Mayo Clinic was funded by NIH grants P50 CA108961 (the Mayo Clinic Brain Tumor SPORE) and RC1 NS068222. Work at University of California, San Francisco was supported by NIH grants R01 CA52689 and UCSF Brain Tumor SPORE, P50CA097257, as well as by grants from the National Brain Tumor Foundation, the UCSF Lewis Chair in Brain Tumor Research and by donations from families and friends of John Berardi, Helen Glaser and Elvera Olsen. We thank the University of Georgia Genome Center

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Distinct germ line polymorphisms underlie glioma morphologic heterogeneity

Section snippets

Mayo Clinic case-control study

Stratification of germ line risk alleles by oligodendroglial components

Discussion

Acknowledgments

Am J Hum Genet

Am J Hum Genet

Am J Pathol

Cancer Cell

Cell

Cell

J Biol Chem

Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors

Cancer Res

Genome-wide association study identifies five susceptibility loci for glioma

Nat Genet

Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility

Nat Genet