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Enciso-Mora, V.* ; Hosking, F.J.* ; di Stefano, A.L.* ; Zelenika, D.* ; Shete, S.* ; Broderick, P.* ; Idbaih, A.* ; Delattre, J.Y.* ; Hoang-Xuan, K.* ; Marie, Y.* ; Labussière, M.* ; Alentorn, A.* ; Ciccarino, P.* ; Rossetto, M.* ; Armstrong, G.* ; Liu, Y.* ; Gousias, K.* ; Schramm, J.* ; Lau, C.* ; Hepworth, S.J.* ; Schoemaker, M.* ; Strauch, K. ; Müller-Nurasyid, M. ; Schreiber, S.* ; Franke, A.* ; Moebus, S.* ; Eisele, L.* ; Swerdlow, A.* ; Simon, M.* ; Bondy, M.* ; Lathrop, M* ; Sanson, M.* ; Houlston, R.S.*

Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222.

Br. J. Cancer 108, 2178-2185 (2013)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Inherited Susceptibility ; Glioma ; Risk; Genome-wide Association ; Risk ; Population ; Cancer ; Tumors ; Polymorphism ; Metaanalysis ; Genetics ; Disease ; Adults
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0007-0920
e-ISSN 1532-1827
Journal British Journal of Cancer BJC
Quellenangaben Volume: 108, Issue: 10, Pages: 2178-2185 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504100-001
DOI 10.1038/bjc.2013.155
WOS ID WOS:000319561300033
Scopus ID 84878596486
Erfassungsdatum 2013-07-05
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