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.

Genome-Wide Association Studies in Glioma

“…The association with glioma was confirmed in an independent European study (32). To refine the association signal at 8q24.21 in glioma, the region was fine-mapped by sequencing as well as statistical imputation of preexisting GWAS datasets.…”

“…27). A number of additional studies have replicated the association between rs78378222 and glioma risk (20, 32, 113, 114). …”

Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case–Control Study

“…Similarly, the lack of a positive confirmation of associations between rs2736100 (5p15.33; TERT) and both glioma overall (P ¼ 0.0655) and GBM (P ¼ 0.0788) is likely attributable to small sample sizes, especially when factoring in previous results indicating an association between rs2736100 and glioma risk among incident cohort cases (11). Furthermore, the 17p13.1 (TP53) variant rs78378222 has previously been associated with risk for both GBM and non-GBM tumors (31). In this study, we found an association with risk for glioma overall (i.e., all glioma diagnoses, not including ependymoma), but it did not replicate specifically for GBM (P ¼ 0.1012).…”

<b>Prevalence of low-penetrant germline </b><i><b>TP53</b></i><b> D49H mutation in Japanese cancer </b><b>patients </b>

“…To date, TP53 database of the International Agency for Research on Cancer (IARC) collected several hundred pedigrees having Li-Fraumeni/Li-Fraumenilike syndromes, with the genetic status of germline TP53 mutations (8,16). We also found that a large number of publications was dealing with cancer patients with the germline TP53 mutations showing no typical features of Li-Fraumeni/Li-Fraumeni-like syndromes; a part of these cases could be explained by the low penetrance of the germline TP53 mutations (2,23) . We investigated the germline TP53 variations in cancer patients belonging to the Project HOPE cohort through several steps.…”