AUTHOR=Niu Lei , Liu Langbiao , Cai Jun 

TITLE=A novel strategy for precise prognosis management and treatment option in colon adenocarcinoma with TP53 mutations

JOURNAL=Frontiers in Surgery

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/surgery/articles/10.3389/fsurg.2023.1079129

DOI=10.3389/fsurg.2023.1079129

ISSN=2296-875X

ABSTRACT=<sec><title>Background</title><p>TP53 is one of the most frequent mutated genes in colon cancer. Although colon cancer with TP53 mutations has a high risk of metastasis and worse prognosis generally, it showed high heterogeneity clinically.</p></sec><sec><title>Methods</title><p>A total of 1,412 colon adenocarcinoma (COAD) samples were obtained from two RNA-seq cohorts and three microarray cohorts, including the TCGA-COAD (<italic>N</italic> = 408), the CPTAC-COAD (<italic>N</italic> = 106), GSE39582 (<italic>N</italic> = 541), GSE17536 (<italic>N</italic> = 171) and GSE41258 (<italic>N</italic> = 186). The LASSO-Cox method was used to establish the prognostic signature based on the expression data. The patients were divided into high-risk and low-risk groups based on the median risk score. The efficiency of the prognostic signature was validated in various cohorts, including TP53-mutant and TP53 wild-type. The exploration of potential therapeutic targets and agents was performed by using the expression data of TP53-mutant COAD cell lines obtained from the CCLE database and the corresponding drug sensitivity data obtained from the GDSC database.</p></sec><sec><title>Results</title><p>A 16-gene prognostic signature was established in TP53-mutant COAD. The high-risk group had significantly inferior survival time compared to the low-risk group in all TP53-mutant datasets, while the prognostic signature failed to classify the prognosis of COAD with TP53 wild-type properly. Besides, the risk score was the independent poor factor for the prognosis in TP53-mutant COAD and the nomogram based on the risk score was also shown good predictive efficiency in TP53-mutant COAD. Moreover, we identified SGPP1, RHOQ, and PDGFRB as potential targets for TP53-mutant COAD, and illuminated that the high-risk patients might benefit from IGFR-3801, Staurosporine, and Sabutoclax.</p></sec><sec><title>Conclusion</title><p>A novel prognostic signature with great efficiency was established especially for COAD patients with TP53 mutations. Besides, we identified novel therapeutic targets and potential sensitive agents for TP53-mutant COAD with high risk. Our findings provided not only a new strategy for prognosis management but also new clues for drug application and precision treatment in COAD with TP53 mutations.</p></sec>