Abstract 37: TP53 coding and noncoding variants in cancer susceptibility: From Li-Fraumeni syndrome to Lynch syndrome

The present study is to generate a mouse model of a p53 noncoding germline polymorphism that predisposes human carriers to multiple types of cancer. p53, encoded by TP53, is recognized as the guardian of the human genome. Three distinct sets of alterations occur at the TP53 locus, which spans ∼20kb in the human genome: tumor-associated somatic mutations, germline mutations causing Li-Fraumeni syndrome, and germline polymorphisms. The first two types of TP53 mutations occur in the coding sequence (CDS) and produce mutant p53 proteins that lack most or all of the normal tumor suppressive functions and often confer oncogenic properties. By contrast, only a few of the >200 naturally occurring germline variants of TP53 in human populations cause measurable perturbation of p53 function. More than 90% of TP53 germline variants occur in 10 introns alleged to have no cancer-related biological consequences. None of the 20 variants in the TP53 CDS have been reproducibly linked to cancer predisposition. Genome-wide association studies (GWAS) reported no significant association between any germline TP53 polymorphism and any cancer with a P value ≤ 10-7 (a threshold for genome-wide significance) until a single nucleotide polymorphism (SNP) rs78378222 was found to be associated strongly with skin basal cell carcinoma. rs78378222 is located in the fifth nucleotide of the TP53 polyadenylation signal (PAS) that is required for polyadenylation machinery recognition and subsequent cleavage and polyadenylation of mRNA. The risk-associated minor allele is a “C”, resulting in an alternative PAS (AATACA) instead of the canonical PAS (AATAAA). This variant is also associated with an increased risk of colorectal adenoma, prostate cancer, glioma, and esophageal squamous cell carcinoma. It is notable that cancer susceptibility of this p53 noncoding variant does not mirror that of p53 coding germline mutations (patients with Li-Fraumeni syndrome develop predominantly breast cancer, brain tumors, acute leukemia, sarcoma, and adrenal cortical carcinoma). Specifically, carriers with the p53 PAS variant are not predisposed to breast cancer. The p53 PAS variant is uniquely positioned among cancer-susceptibility alleles: (i) low frequency (∼2% in the general populations), (ii) intermediate cancer risk (odds ratio 1.39-3.54), and (iii) predisposing carriers to multiple types of cancer. To mimic this naturally occurring human variant, we have generated a mouse line with a p53 gene carrying the alternative PAS (AATACA) using zinc-finger nuclease technology. The resultant mutant p53 allele is termed p531755C as the 1755th nucleotide of mouse p53 reference mRNA is the ortholog of human rs78378222. We demonstrate that heterozygote p53+/1755C and homozygote p531755C/1755C mice treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) developed more colon tumors than the p53+/+ controls and homozygous mice developed more advanced tumors than heterozygous mice. With data from murine tumorigenesis and human epidemiology, we propose that this p53 noncoding germline variant is a cancer susceptibility allele associated with Lynch syndrome rather than Li-Fraumeni syndrome. Citation Format: Qipan Deng, Yong Li. TP53 coding and noncoding variants in cancer susceptibility: From Li-Fraumeni syndrome to Lynch syndrome. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 37. doi:10.1158/1538-7445.CANSUSC14-37