期刊
BRITISH JOURNAL OF CANCER
卷 108, 期 10, 页码 2178-2185出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2013.155
关键词
inherited susceptibility; glioma; risk
类别
资金
- Cancer Research UK [C1298/A8362]
- Bobby Moore Fund
- Wellcome Trust
- DJ Fielding Medical Research Trust
- European Union Fifth Framework Program 'Quality of life and Management of Living Resources' [QLK4-CT-1999-01563]
- International Union against Cancer (UICC)
- Mobile Manufacturers' Forum
- Mobile Telecommunications and Health Research (MTHR) Programme
- Northern UK Centre
- Health and Safety Executive, Department of Health and Safety Executive
- UK Network Operators
- NIH [5R01 CA119215, 5R01 CA070917]
- American Brain Tumor Association
- National Brain Tumor Society
- Delegation a la Recherche Clinique [MUL03012]
- Association pour la Recherche sur les Tumeurs Cerebrales (ARTC)
- Institut National du Cancer (INCa) [PL046]
- French Ministry of Higher Education and Research
- Deutsche Forschungsgemeinschaft [Si552, Schr285]
- Deutsche Krebshilfe [70-2385-Wi2, 70-3163-Wi3, 10-6262]
- BONFOR
- Wellcome Trust [076113, 085475]
- German Federal Ministry of Education and Research (BMBF)
- Helmholtz Zentrum Munchen
- German Research Center for Environmental Health, Neuherberg
- German National Genome Research Network (NGFN)
- Munich Center of Health Sciences (MC Health) as part of LMUinnovativ
- GSM Association
Background: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. Methods: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. Results: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P = 6.86 x 10(-24), minor allele frequency similar to 0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non- GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. Conclusion: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.
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