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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, Surrey SM2 5NG, UK.
authors.forename: V
authors.initials: V
authors.lastname: Enciso-Mora
authors.forename: F J
authors.initials: FJ
authors.lastname: Hosking
authors.forename: A L
authors.initials: AL
authors.lastname: Di Stefano
authors.forename: D
authors.initials: D
authors.lastname: Zelenika
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authors.lastname: Broderick
authors.forename: A
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authors.lastname: Idbaih
authors.forename: J-Y
authors.initials: JY
authors.lastname: Delattre
authors.forename: K
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authors.lastname: Hoang-Xuan
authors.forename: Y
authors.initials: Y
authors.lastname: Marie
authors.forename: M
authors.initials: M
authors.lastname: Labussière
authors.forename: A
authors.initials: A
authors.lastname: Alentorn
authors.forename: P
authors.initials: P
authors.lastname: Ciccarino
authors.forename: M
authors.initials: M
authors.lastname: Rossetto
authors.forename: G
authors.initials: G
authors.lastname: Armstrong
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Gousias
authors.forename: J
authors.initials: J
authors.lastname: Schramm
authors.forename: C
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authors.lastname: Lau
authors.forename: S J
authors.initials: SJ
authors.lastname: Hepworth
authors.forename: M
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authors.lastname: Schoemaker
authors.forename: K
authors.initials: K
authors.lastname: Strauch
authors.forename: M
authors.initials: M
authors.lastname: Müller-Nurasyid
authors.forename: S
authors.initials: S
authors.lastname: Schreiber
authors.forename: A
authors.initials: A
authors.lastname: Franke
authors.forename: S
authors.initials: S
authors.lastname: Moebus
authors.forename: L
authors.initials: L
authors.lastname: Eisele
authors.forename: A
authors.initials: A
authors.lastname: Swerdlow
authors.forename: M
authors.initials: M
authors.lastname: Simon
authors.forename: M
authors.initials: M
authors.lastname: Bondy
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.forename: M
authors.initials: M
authors.lastname: Sanson
authors.forename: R S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D001932:Brain Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005910:Glioma / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D026721:RNA 3' End Processing / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology; D014481:United States / Q000453:epidemiology
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53