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. 2013 May 28;108(10):2178-85.
doi: 10.1038/bjc.2013.155. Epub 2013 Apr 9.

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

V Enciso-Mora  1 , F J Hosking, A L Di Stefano, D Zelenika, S Shete, P Broderick, A Idbaih, J-Y Delattre, K Hoang-Xuan, Y Marie, M Labussière, A Alentorn, P Ciccarino, M Rossetto, G Armstrong, Y Liu, K Gousias, J Schramm, C Lau, S J Hepworth, M Schoemaker, K Strauch, M Müller-Nurasyid, S Schreiber, A Franke, S Moebus, L Eisele, A Swerdlow, M Simon, M Bondy, M Lathrop, M Sanson, R S Houlston
Affiliations

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

V Enciso-Mora et al. Br J Cancer. .

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.

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Figures

Figure 1
Figure 1
Case–control association plot for glioma and genomic structure of the chromosome 17p13.1 region (A) All glioma, (B) GBM, (C) non-GBM tumours. Overview of single-point SNP association results of both genotyped (triangles) and imputed (circles) SNPs are shown with recombination rates within the region. The region shown is chr17:7,471,719-7,678,811 (hg18 Built 36). −log10 P values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The top genotyped SNP in each combined analysis is a large CIRCLE and is rs78378222. The colour intensity of each symbol reflects the extent of LD with the top genotyped SNP, from white (r2=0) to dark gray (r2=1.0). Genetic recombination rates (cM/Mb), estimated using HapMap CEU samples, are shown with a light blue line. Also shown are the relative positions of genes and transcripts mapping to the region of association.
Figure 2
Figure 2
Association between glioma risk and rs78378222, for all glioma, GBM and non-GBM. Summary of association results for rs78378222. (A–C) Forest plots of rs78378222 per allele odds ratio (OR) for (A) all glioma, (B) GBM and (C) non-GBM. The x axis corresponds to the OR. Horizontal lines represent 95% confidence intervals. Each box represents the OR point estimate and its area is proportional to the statistical weight of the study. The diamonds (and broken lines) represent the summary odds ratios obtained from fixed-effect pooled analysis with 95% confidence intervals given by their widths. The unbroken vertical line is at the null value (OR=1.0). For all glioma, the MAFs for each study are: French cases: 0.024, French controls: 0.008, German cases: 0.023, German controls: 0.015, USA cases: 0.032, USA controls: 0.012, UK cases: 0.030, UK controls: 0.014.
Figure 3
Figure 3
Association between glioma risk and rs78378222, for grade II, III and IV glioma. Summary of association results for rs78378222. (A–C) Forest plots of rs78378222 per allele odds ratio (OR) for (A) grade II (B) Grade III and (C) Grade IV glioma. The x axis corresponds to the OR. Horizontal lines represent 95% confidence intervals. Each box represents the OR point estimate and its area is proportional to the statistical weight of the study. The diamonds (and broken lines) represent the summary odds ratios obtained from fixed-effect pooled analysis with 95% confidence intervals given by their widths. The unbroken vertical line is at the null value (OR=1.0).
Figure 4
Figure 4
Kaplan–Meier curves for glioma patients according to rs78378222 genotype. Survival curves for the common homozygotes (AA) are shown as a solid line. The dashed line depicts the survival curve for the heterozygotes (AC) and rare homozygotes (CC). (A) French grade II cases (HR=0.95, 95% CI: 0.40–2.28); (B) French grade III cases (HR=1.51, 95% CI: 0.74–3.09); (C) French grade IV cases (HR=1.24, 95% CI: 0.70–2.18); (D) German grade II cases (HR=3.11, 95% CI: 0.27–35.88); (E) German grade III cases (HR=NA); (F) German grade IV cases (HR=1.23, 95% CI: 0.68–2.21).
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