Genomic Differences and Distinct TP53 Mutation Site-Linked Chemosensitivity in Early- and Late-Onset Gastric Cancer

Area of Science:

• Genomic medicine
• Oncology
• Cancer genomics

Background:

• Gastric cancer (GC) in younger patients often presents with aggressive behavior and poorer prognosis.
• Clinical differences in GC may be linked to oncogenic gene variations, but genetic distinctions between early- and late-onset GC remain unclear.

Purpose of the Study:

• To compare the genetic profiles of early- and late-onset GC.
• To evaluate the impact of genetic differences on treatment outcomes, particularly TP53 mutations and response to platinum-based chemotherapy.

Main Methods:

• Analysis of genetic data from 1284 GC patients (early-onset ≤ 39 years, n=143; late-onset ≥ 65 years, n=1141) from the Japanese C-CAT database.
• Assessment of TP53 mutation influence on time to treatment failure (TTF) with platinum-based chemotherapy.
• In vitro evaluation of cancer cell sensitivity to oxaliplatin based on TP53 mutation sites.

Main Results:

• Distinct genetic profiles were observed between early- and late-onset GC, with fewer neoantigen-associated changes in early-onset cases.
• TP53 mutation sites differed, with R175H more frequent in early-onset and R273 in late-onset GC.
• The TP53 R175H mutation correlated with higher oxaliplatin sensitivity in vitro and longer TTF (17.3 vs. 7.0 months) in early-onset patients with TP53 mutations.

Conclusions:

• Genomic disparities, specifically in TP53 mutation profiles, exist between early- and late-onset GC.
• These findings underscore the necessity for developing age-specific treatment strategies for gastric cancer.