64 - Freie Mitteilung
16. Mai 2019, 13:45 - 15:15, Szenario 1, 5. OG
Inherited polymorphic p53 response elements in the human genome interact with somatic p53 mutations to affect tumour-related survival: A pan-cancer analysis
L. F. Grochola1, 2, S. Ntaoulas1, C. Dimitrakopoulos2, P. Zhang3, N. Seeger1, S. Breitenstein1, L. Xiong3, G. Bond3, Presenter: L. F. Grochola1, 2 (1Winterthur, 2Zurich, 3Oxford/UK)
p53 is a transcription factor that acts as a tumour suppressor in a wide range of human cancers. This key role of p53 implies that inherited polymorphisms in functional p53 binding sites could affect cancer progression. The identification of such variants and their possible interaction with somatic p53 mutations has the potential to identify tumours with an aggressive biological phenotype and guide personalised treatment strategies.
In an integrative analysis, genome-wide data sets of genetic variation, in vitro p53 occupancy and p53 retriever algorithm scores, as well as signatures of natural selection were utilised to uncover single-nucleotide polymorphisms (SNPs) in functional p53 response elements (RE) that are likely to alter the transactivation potential of p53. The effect of p53 RE SNPs on cancer-related survival was analysed using the The Cancer Genome Atlas (TCGA) database in colorectal, lung, breast and brain cancers, which constitute the four most common p53-dependent tumour types in humans. In total, 3689 patients with known somatic p53 mutation status and an in-depth characterisation of germline genetic variation who underwent a surgical intervention were included in the study. We analysed the associations of the identified p53 RE SNPs with tumour-related survival using Kaplan-Meier and Cox multivariate regression analyses and searched for clinically-relevant potential interactions of the polymorphic p53 REs with the somatic p53 mutation status of the patients´ tumours.
In this genome-wide analysis, we present a comprehensive list of polymorphisms that reside in functional p53 response elements of genes regulated by this key tumour suppressor and are likely to alter the binding affinity as well as transcriptional regulation of p53. Those SNPs show significant allelic differences in tumour-related death after multiple hypothesis correction in each of the four analysed cancer types predominantly in a p53 mutation status-dependent manner.
The data suggests that inherited polymorphic p53 REs affect transcriptional regulation of p53 and interact with somatic mutations in this gene to affect cancer survival. The identified polymorphisms in functional p53 REs have the potential to serve as predictive biomarkers of cancer survival and could help guide personalised treatment strategies in a wide range of p53-dependent tumours.