早发性和晚发性胃癌的基因组差异及与不同TP53突变位点相关的化疗敏感性

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

作者信息

Kamio Tomohiro, Kono Yoshiyasu, Hirosuna Kensuke, Ozato Toshiki, Yamamoto Hideki, Hirasawa Akira, Ennishi Daisuke, Tomida Shuta, Toyooka Shinichi, Otsuka Motoyuki

机构信息

Department of Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

出版信息

Cancer Med. 2025 Apr;14(8):e70793. doi: 10.1002/cam4.70793.

DOI:10.1002/cam4.70793

PMID:40249206

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12007182/

Abstract

BACKGROUND

Gastric cancer (GC) in younger patients often exhibits aggressive behavior and a poorer prognosis than that in older patients. Although the clinical differences may stem from oncogenic gene variations, it is unclear whether genetic differences exist between these groups. This study compared the genetic profiles of early- and late-onset GC and evaluated their impact on treatment outcomes.

METHODS

We analyzed genetic data from 1284 patients with GC in the Japanese nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, comparing early-onset (≤ 39 years; n = 143) and late-onset (≥ 65 years; n = 1141) groups. The influence of TP53 mutations on the time to treatment failure (TTF) with platinum-based chemotherapy and the sensitivity of cancer cells with different TP53 mutation sites to oxaliplatin were assessed in vitro.

RESULTS

Early- and late-onset GC showed distinct genetic profiles, with fewer neoantigen-associated genetic changes observed in early-onset cases. In particular, TP53 has distinct mutation sites; R175H and R273 mutations are more frequent in early- and late-onset GC, respectively. The R175H mutation showed higher sensitivity to oxaliplatin in vitro, consistent with the longer TTF in early-onset patients (17.3 vs. 7.0 months, p = 0.013) when focusing on the patients with TP53 mutations.

CONCLUSION

Genomic differences, particularly in TP53 mutation sites, between early- and late-onset GC support the need for age-specific treatment strategies.

摘要

背景

年轻患者的胃癌（GC）通常表现出侵袭性更强的行为，且预后比老年患者更差。尽管临床差异可能源于致癌基因变异，但尚不清楚这些群体之间是否存在基因差异。本研究比较了早发型和晚发型GC的基因谱，并评估了它们对治疗结果的影响。

方法

我们分析了日本全国癌症基因组学与先进治疗中心（C-CAT）数据库中1284例GC患者的基因数据，比较了早发型（≤39岁；n = 143）和晚发型（≥65岁；n = 1141）两组。在体外评估了TP53突变对铂类化疗治疗失败时间（TTF）的影响以及不同TP53突变位点的癌细胞对奥沙利铂的敏感性。

结果

早发型和晚发型GC显示出不同的基因谱，早发型病例中观察到的新抗原相关基因变化较少。特别是，TP53有不同的突变位点；R175H和R273突变分别在早发型和晚发型GC中更常见。R175H突变在体外对奥沙利铂表现出更高的敏感性，这与聚焦于TP53突变患者时早发型患者较长的TTF一致（17.3个月对7.0个月，p = 0.013）。