Identification of FEN1 as a prognostic marker and novel therapeutic target in gastric cancer harboring TP53 mutations.

Authors

null

Ting Deng

Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

Organizations

Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

Research Funding

No funding received
None.

Background: As a common tumor suppressor gene, TP53 gene mutation leads to persistent activation of multiple downstream effectors that drive the cancer phenotype. Approximately 50% of gastric cancer (GC) patients harbor TP53 mutations, which confer stronger tumor biology and shorter overall survival (OS). Given that TP53-mutated proteins have proven difficult to target directly, identifying genes that function closely with TP53 and targeting these genes appears to be a promising therapeutic strategy for TP53-mutated GC patients. Methods: TP53 functionally sensitive genes were identified by evaluating the correlation between gene-dependent scores from CRISPR knockout screens and TP53 mRNA expression in TP53 mutant GC cell lines in the Cancer Cell Line Encyclopedia (CCLE) database. If the correlation coefficient is ≥0.6, the gene was considered as TP53 functional sensitive gene. Then TP53 functionally sensitive genes associated with prognosis were screened out in The Cancer Genome Atlas (TCGA). PockDrug-Server was used to predict drug susceptibility of candidate genes. Results: The results showed that in 9 GC cell lines with TP53 mutations and 14 with TP53 wild-type, 4 genes (KLF5, FEN1, CCNA2, CCNB1) were identified as TP53 functional sensitive genes. Among the 4 genes, only FEN1 expression was significantly correlated with OS (HR=1.85, 95CI 1.06−3.26, P=0.029). Multivariate Cox regression analysis showed that high FEN1 expression was an independent predictor of prognosis in TP53-mutated GC. Pocket druggability prediction analysis presented that FEN1 had 8 drug-able pockets, four of which all have a druggability score of 0.8 or higher, including one pocket with a score of 1. Conclusions: These findings suggested that FEN1 was promising prognostic marker and therapeutic target in TP53-mutated GC.

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Abstract Details

Meeting

2023 ASCO Annual Meeting

Session Type

Publication Only

Session Title

Publication Only: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary

Track

Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary

Sub Track

Esophageal or Gastric Cancer - Advanced/Metastatic Disease

Citation

J Clin Oncol 41, 2023 (suppl 16; abstr e16057)

DOI

10.1200/JCO.2023.41.16_suppl.e16057

Abstract #

e16057

Abstract Disclosures

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