@article{ad988bc8c5144996b18e0699088b2cdb,
title = "Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222",
abstract = "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 × 10-24, minor allele frequency ∼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.",
author = "V. Enciso-Mora and Hosking, {F. J.} and {Di Stefano}, {A. L.} and D. Zelenika and S. Shete and P. Broderick and A. Idbaih and Delattre, {J. Y.} and K. Hoang-Xuan and Y. Marie and M. Labussi{\`e}re and A. Alentorn and P. Ciccarino and M. Rossetto and G. Armstrong and Y. Liu and K. Gousias and J. Schramm and C. Lau and Hepworth, {S. J.} and M. Schoemaker and K. Strauch and M. M{\"u}ller-Nurasyid and S. Schreiber and A. Franke and S. Moebus and L. Eisele and A. Swerdlow and M. Simon and M. Bondy and M. Lathrop and M. Sanson and Houlston, {R. S.}",
note = "Funding Information: We are grateful to all the patients and individuals for their participation and we also thank the clinicians and other hospital staff, cancer registries and study staff in respective centres who contributed to the blood sample and data collection. For the UK GWA study, we acknowledge the participation of the clinicians and other hospital staff, cancer registries, study staff and funders who contributed to the blood sample and data collection for this study as listed in Hepworth et al (2006). MD Anderson acknowledges the work on the USA GWA study of Phyllis Adatto, Fabian Morice, Hui Zhang, Victor Levin, Alfred WK Yung, Mark Gilbert, Raymond Sawaya, Vinay Puduvalli, Charles Conrad, Fredrick Lang and Jeffrey Weinberg from the Brain and Spine Center. For the German GWA study, we are indebted to B Harzheim (Bonn) and Dr A M{\"u}ller-Erkwoh (Bonn) for help with the acquisition of clinical data and R Mahlberg (Bonn) who provided technical support. The UK GWA study made use of control genotyping data generated by the Wellcome Trust Case–Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. The US GWA study made use of control genotypes from the CGEMS prostate and breast cancer studies. A full list of the investigators who contributed to the generation of the data is available from http:// cgems.cancer.gov/. French controls were taken from the SU.VI.-MAX study. The German GWA study made use of genotyping data from three population control sources: KORA-gen, The Heinz-Nixdorf RECALL study and POPGEN. We are extremely grateful to all investigators who contributed to the generation of these data sets. In the United Kingdom, funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund), the Wellcome Trust and the DJ Fielding Medical Research Trust. The UK INTERPHONE study was supported by the European Union Fifth Framework Program {\textquoteleft}Quality of life and Management of Living Resources{\textquoteright} (QLK4-CT-1999-01563) and the International Union against Cancer (UICC). The UICC received funds from the Mobile Manufacturers{\textquoteright} Forum and GSM Association. Provision of funds via the UICC was governed by agreements that guaranteed INTERPHONE{\textquoteright}s scientific independence (http://www.iarc.fr/ENG/Units/RCAd.html). The UK centres were also supported by the Mobile Telecommunications and Health Research (MTHR) Programme and the Northern UK Centre was supported by the Health and Safety Executive, Department of Health and Safety Executive and the UK Network Operators. The views expressed in this paper are not necessarily those of the funders. In the United States, funding was provided by NIH grants 5R01(CA119215&5R01 CA070917). Support was also obtained from the American Brain Tumor Association and the National Brain Tumor Society. In France, funding was provided by the D{\'e}l{\'e}gation {\`a} la Recherche Clinique (MUL03012), the Association pour la Recherche sur les Tumeurs C{\'e}r{\'e}brales (ARTC), the Institut National du Cancer (INCa; PL046) and the French Ministry of Higher Education and Research. In Germany, funding was provided to MS and JS by the Deutsche Forschungs-gemeinschaft (Si552, Schr285), the Deutsche Krebshilfe (70-2385-Wi2,70-3163-Wi3,10-6262) and BONFOR. Funding for the WTCCC was provided by the Wellcome Trust (076113&085475). The KORA Augsburg studies are supported by grants from the German Federal Ministry of Education and Research (BMBF) and were mainly financed by the Helmholtz Zentrum M{\"u}nchen, German Research Center for Environmental Health, Neuherberg. This work was financed by the German National Genome Research Network (NGFN) and supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ.",
year = "2013",
month = may,
doi = "10.1038/bjc.2013.155",
language = "English (US)",
volume = "108",
pages = "2178--2185",
journal = "British journal of cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "10",
}