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

Abstract

The causes of glioblastoma and other gliomas remain obscure1,2. To discover new candidate genes influencing glioma susceptibility, we conducted a principal component–adjusted3 genome-wide association study (GWAS) of 275,895 autosomal variants among 692 adult high-grade glioma cases (622 from the San Francisco Adult Glioma Study (AGS) and 70 from the Cancer Genome Atlas (TCGA))4 and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)). For replication, we analyzed the 13 SNPs with P < 10−6 using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On 9p21, rs1412829 near CDKN2B had discovery P = 3.4 × 10−8, replication P = 0.0038 and combined P = 1.85 × 10−10. On 20q13.3, rs6010620 intronic to RTEL1 had discovery P = 1.5 × 10−7, replication P = 0.00035 and combined P = 3.40 × 10−9. For both SNPs, the direction of association was the same in discovery and replication phases.

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Figure 1: Distribution of P values from principal component–adjusted logistic regression additive model across the genome for high-grade glioma cases versus controls.
Figure 2: Map of the associated 9p21 region in high-grade glioma.

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Acknowledgements

Work at University of California, San Francisco (UCSF) has been supported by US National Institutes of Health grants R01CA52689 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 J. Berardi, H. Glaser and E. Olsen. J.S.C. was also supported by a fellowship from the National Cancer Institute (grant R25 CA 112355). Work at the Mayo Clinic has been supported by the Mayo Clinic Brain Tumor SPORE (NIH P50 CA108961), the Mayo Clinic Comprehensive Cancer Center (P30 CA15083) and the Bernie and Edith Waterman Foundation. The San Francisco Adult Glioma Study thanks the Northern California Cancer Center for identifying glioma cases; we also thank K. Aldape for pathology review and the pathology departments of Alexian, Alta Bates, Brookside, California Pacific, Doctors Pinole, Eden, El Camino, Good Samaritan, Highland, John Muir, Kaiser Redwood City, Kaiser San Francisco, Kaiser Santa Teresa, Los Gatos, Los Medanos, Marin General, Merrithew, Mills Peninsula, Mt. Diablo Hospital, Mt. Zion, Naval Hospital, O'Connor, Ralph K Davies, Saint Louise, San Francisco General, San Jose, San Leandro, San Mateo County, San Ramon Valley, Santa Clara Valley, Sequoia, Seton, St. Francis, St. Luke's, St. Rose, Stanford, Summit, UC San Francisco, Valley Livermore, Veterans Palo Alto, Veterans SF, and Washington Hospitals and Medical Centers for providing tumor specimens for review. Genotyping services for San Francisco study subjects were provided by deCODE Genetics, Iceland. The company provided SNP and normalized CNV data and technical support in data analysis, including conference call tutorials in the use of the Disease Miner Software. We thank B. Scheithauer and C. Gianinni for their careful histological review of all the primary high-grade gliomas collected at the Mayo Clinic for this study. The Mayo Clinic Comprehensive Cancer Center Biospecimens and Processing (TACMA), Gene Analysis, Biostatistics and Bioinformatics Shared Resources were essential for the success of this study. We also thank K. Kelsey for helpful suggestions on genotyping and interpretation of results, N. Risch for very helpful suggestions on this paper and S. Sen for helpful discussions and suggestions on statistical methods. Some computations were performed using the UCSF Biostatistics High Performance Computing System.

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Contributions

M.W. was the overall UCSF study principal investigator who was responsible for subject recruitment, oversaw all analyses and wrote parts of and synthesized the paper. R.B.J. was the overall co-principal investigator of the Mayo study who oversaw the entire study (particularly laboratory quality control), interpreted the results and wrote parts of the paper. J.S.C. was the UCSF epidemiologist who contributed to development of the analysis plan, conducted statistical analyses and wrote parts of the paper. R.-F.Y. was the UCSF biostatistician who oversaw and conducted statistical analyses of the discovery phase and wrote parts of the paper. Y.X. was the UCSF biostatistician who conducted statistical analyses of the discovery and combined phases and wrote parts of the paper. P.A.D. was the Mayo statistician who performed all Mayo data analysis. K.V.B. was the Mayo lead statistician who participated in study design and the analysis plan. M.B. was the principal investigator of the UCSF Brain Tumor SPORE and a clinical collaborator who provided access for subject recruitment. J.C.B. was the Mayo neuro-oncologist who led subject recruitment. S.C. was the co-director of the UCSF neuro-oncology clinic who assisted in subject recruitment. C.G. was the Mayo pathologist who verified all pathologic diagnosis of Mayo cases. C.H. was the Mayo laboratory technologist responsible for specimen preparation for genotyping. T.M.K. was the Mayo laboratory manager responsible for specimen storage and retrieval. M.L.K. provided statistical support for all Mayo analyses. D.H.L. was the Mayo neuro-oncologist who facilitated subject enrollment and medical record data collection. L.M. was the UCSF project coordinator responsible for subject recruitment and preparation of datasets for analyses, and also conducted analyses. B.P.O. was the principal investigator of Mayo brain tumor SPORE and neurologist who facilitated subject enrollment and medical record data collection. J.P. was the UCSF laboratory manager responsible for specimen storage, retrieval and preparation for genotyping. A.R.P. was the UCSF/Gladstone bioinformatician who participated in selecting the genotyping platform, developing the analytical plan and reviewing the paper. M.P. was the co-director of the UCSF neuro-oncology clinic who assisted in subject recruitment. C.Q. participated in subject recruitment and pathology specimen accrual from Kaiser Permanente Northern California. T.R. was the UCSF project coordinator responsible for subject recruitment, prepared datasets for analyses, conducted analyses and wrote parts of paper. A.L.R. was the Mayo project coordinator responsible for subject recruitment. I.S. was the UCSF bioinformatician who participated in developing the analytical plan, data analysis and interpreting results. T.T. was the UCSF neuropathologist who participated in subject identification, accrual and development of the analytical strategy. J.W. was the UCSF epidemiologist who participated in choice of genotyping platform and development of the analytical strategy and oversaw sample preparation. P.Y. was the overall co-principal investigator of the Mayo study who oversaw the entire study (particularly study design for subject recruitment, control enrollment, data quality control and analyses), interpreted results and wrote parts of the paper. J.K.W. was the UCSF study co-principal investigator who oversaw all aspects of laboratory work, participated in study design, subject accrual and development of the analysis plan, and wrote the discussion portion of the paper.

Corresponding author

Correspondence to Margaret Wrensch.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–6 and Supplementary Figures 1–8 (PDF 1023 kb)

Supplementary Table 7

SNPs with P < 0.001 for association with high grade glioma comparing cases from San Francisco Bay Area Adult Glioma Study, 1997-2006 (AGS) and the Cancer Genome Atlas (TCGA) to AGS and Illumina controls (iControls) (XLS 140 kb)

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Wrensch, M., Jenkins, R., Chang, J. et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet 41, 905–908 (2009). https://doi.org/10.1038/ng.408

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