Abstract
Mutations in the tumor suppressor gene TP53 are associated with a variety of cancers. Therefore, it is important to know the occurrence and prognostic effects of TP53 mutations in certain cancers. Over 29,000 cases from the April 2016 release of the International Agency for Research on Cancer (IARC) TP53 Database were analyzed to determine the distribution of germline and somatic mutations in the TP53 gene. Subsequently, 7,893 cancer cases were compiled in cBioPortal for Cancer Genomics from the 33 most recent The Cancer Genome Atlas (TCGA) studies to determine the prevalence of TP53 mutations in cancers and their effects on survival and disease-free survival times. The data were analyzed, and it was found that the majority of TP53 mutations were missense and the major mutational hotspots were located at codons 248, 273, 175, and 245 in exons 4-8 for somatic mutations with the addition of codon 337 and other mutations in exons 9-10 for germline mutations. Out of 33 TGCA studies, the effects of TP53 mutations were statistically significant in nine cancers (lung adenocarcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, acute myeloid leukemia, clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, uterine endometrial carcinoma, and thymoma) for survival time and in five cancers (pancreatic adenocarcinoma, hepatocellular carcinoma, chromophobe RCC, acute myeloid leukemia, and thymoma) for disease-free survival time. It was also found that the most common p53 mutation in hepatocellular carcinomas (R249S) was a much better indicator for poor prognosis than TP53 mutations as a whole. In addition, in cases of ovarian serous cystadenocarcinoma, the co-occurrence of TP53 and BRCA mutations resulted in longer survival and disease-free survival times than the presence of neither TP53 nor BRCA mutations. TP53 mutations are potential prognostic markers that can be used to further improve the accuracy of predicting survival and disease-free survival times of cancer patients.
Highlights
The tumor suppressor gene TP53 encodes for the p53 protein, which serves a role in DNA repair, cell cycle arrest, apoptosis, and other pathways that prevent the development of cancers
We discovered that TP53 mutations in ovarian serous cystadenocarcinomas, which mostly occurred in the DNA-binding domain (DBD), increased the survival and the disease-free survival time of patients, contrary to a study published in 2007 that said “TP53 mutations within the [DBD] have been repeatedly associated with shorter survival” [18]
The data sets of the most recent The Cancer Genome Atlas (TCGA) cancer studies were selected in the portal, which resulted in 33 studies and 7,893 cases in total
Summary
The tumor suppressor gene TP53 encodes for the p53 protein, which serves a role in DNA repair, cell cycle arrest, apoptosis, and other pathways that prevent the development of cancers. The TP53 gene and its corresponding protein are frequently inactivated or partially disabled by mutations that lead to increased risks of developing cancer. The two transactivation domains are encoded in exons 2-4, the DNA-binding domain in exons 48, the tetramerization domain in exons 9-10, and the basic domain in exons 10-11. Each domain of this 393 amino acid protein has its own distinct function
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