TP53 alterations of hormone-naïve prostate cancer in the Chinese population

Abstract

Background Prostate cancer (PCa) shows racial disparity in clinical and genomic characteristics, and Asian patients with PCa often present with more aggressive phenotypes at diagnosis. The ability of TP53 to serve as a prognostic biomarker of PCa has been well studied in Western populations. However, no studies to date have examined the role of TP53 in the disparities of primary hormone-naïve prostate cancer (HNPC) between Chinese and Western populations. Methods We collected prostate tumors and matched normal tissues or blood samples to perform targeted next-generation sequencing of 94 Chinese primary localized HNPC samples, and correlated these genomic profiles with clinical outcomes. The OncoKB knowledge database was used to identify and classify actionable alterations. Results The aberrations of PTEN, CDK12, and SPOP in Chinese HNPC samples were similar to those in the Western samples. However, we demonstrated an association of a high frequency of TP53 alterations (21/94) with a relatively higher percentage of alterations in the Wnt signaling pathway (15/94) in Chinese HNPC. Additionally, we highlighted alterations of LRP1B as accounting for a high proportion of PCa and found more frequent alterations in CDH1 in Chinese PCa. Of these, only CDH1 alteration was associated with rapid biochemical recurrence (BCR). However, we verified that TP53 status was at the core of the genomic alteration landscape in Chinese HNPC with putative driver mutations because of the strong connections with other signaling pathways. The mutually exclusive relationship between alterations in TP53 and Wnt/ CTNNB1 further molecularly characterizes subsets of prostate cancers. Moreover, the alteration of KMT2C was more likely to co-occur with TP53 alteration, indicating a more aggressive phenotype of PCa, which was associated with sensitivity to treatment with poly ADT-ribose polymerase (PARP) inhibitors. Conclusions Detection of TP53 alterations has clinical utility for guiding precision cancer therapy for HNPC, especially in the Chinese population.

A Personalized Genomics Approach of the Prostate Cancer

“…Alteration of TP53 (e.g., [ 66 ]) and another signaling (e.g., [ 67 ]) pathways in the prostate cancer were analyzed by several other groups before, but this is the first time after our knowledge that the analysis goes beyond expression regulation to explore also the expression coordination.…”

Impact of TP53 mutations in Triple Negative Breast Cancer

“…The F270 position within the DNA-binding domain is important for stabilizing the beta-sandwich structure of the p53 protein, and mutation to leucine is predicted to be a druggable target for small molecules to stabilize this type of p53 mutant [30][31][32] . Mutations at the R337 residue have a role in p53 methylation and ubiquitination, and R337L is thought to promote stability and sub-cellular localization of p53 33,34 . To our knowledge, the function of L308P, V274A, and K132R mutations have not been biochemically characterized 35,36 .…”

Cuproptosis-related lncRNA predict prognosis and immune response of lung adenocarcinoma

“…We found a significant decrease in the survival of patients with high TMB (P < 0.05) and an increase in TP53 and TTN expression in patients at high risk. TP53 is a frequently mutated oncogene in human cancers, affecting the development of breast, lung, bladder, esophageal, prostate, pancreatic, and colorectal cancers and is involved in the normal physiology and metabolism of diabetes, liver, and cardiovascular diseases [40][41][42][43][44]. TP53 is also associated with the survival of patients with multiple cancers [45].…”