Abstract
Simple Summary: We investigated the influence of genetic variants, called single nucleotide polymorphisms (SNP) in theTP53tumour suppressor gene, on cancer risk, clinical features andTP53isoform levels. These SNPs were significantly over-represented in cohorts of mixed cancers versus controls, suggesting they confer increased cancer risk. Heterozygosity at rs1042522(GC) and either of the two SNPs rs9895829(TC) and rs2909430(AG) confer up to a 5-fold greater risk of developing cancer. The SNP combinations were associated with high Delta 133TP53 and TP53 beta messenger RNA levels, elevated infiltrating immune cells and shorter patient survival for glioblastoma and prostate cancer. The data suggest that increment 133p53 beta protein levels are increased by the SNPs resulting in increased inflammation which contributes to more aggressive cancers.
We investigated the influence of selectedTP53SNPs in exon 4 and intron 4 on cancer risk, clinicopathological features and expression of TP53 isoforms. The intron 4 SNPs were significantly over-represented in cohorts of mixed cancers compared to three ethnically matched controls, suggesting they confer increased cancer risk. Further analysis showed that heterozygosity at rs1042522(GC) and either of the two intronic SNPs rs9895829(TC) and rs2909430(AG) confer a 2.34-5.35-fold greater risk of developing cancer. These SNP combinations were found to be associated with shorter patient survival for glioblastoma and prostate cancer. Additionally, these SNPs were associated with tumor-promoting inflammation as evidenced by high levels of infiltrating immune cells and expression of the Delta 133 TP53 and TP53 beta transcripts. We propose that these SNP combinations allow increased expression of the Delta 133p53 isoforms to promote the recruitment of immune cells that create an immunosuppressive environment leading to cancer progression.