| 論文種別 | 原著(症例報告除く) |
| 言語種別 | 英語 |
| 査読の有無 | その他(不明) |
| 表題 | FGFR2-IIIc isoform detection reveals prognostic prevalence and a functional link to mesenchymal transition in gastric and gastroesophageal junction cancer. |
| 掲載誌名 | 正式名：ESMO open 略 称：ESMO Open ISSNコード：20597029/20597029 |
| 掲載区分 | 国外 |
| 巻・号・頁 | 10(11),pp.105851 |
| 著者・共著者 | T Hashimoto, N Iida, S Kadowaki, A Makiyama, N Machida, N Takahashi, S Boku, T Kudo, E Oki, K Ohtsubo, T Kawakami, N Okano, Y Komatsu, S Yuki, N Sakamoto, T Kuwata, R Yamashita, M Amisaki, T Shibuki, M Imai, T Fujisawa, Y Nakamura, H Bando, K Shitara, T Yoshino |
| 発行年月 | 2025/11 |
| 概要 | BACKGROUND:Fibroblast growth factor receptor 2 (FGFR2), a therapeutic target for advanced gastric and gastroesophageal junction cancers (GC/GEJCs), exists as two functionally distinct isoforms: FGFR2-IIIb and FGFR2-IIIc. We investigated the clinical significance of FGFR2 splice variant distribution in advanced GC/GEJCs and its implications for therapeutic targeting.PATIENTS AND METHODS:Whole-transcriptome sequencing was carried out on 235 patients with advanced GC/GEJCs enrolled in MONSTAR-SCREEN-2 (UMIN000043899). FGFR2-IIIc proportion was quantified using splice junction analysis, and its association with clinical outcomes was evaluated through survival analysis, comprehensive molecular profiling, and longitudinal assessment of treatment-induced isoform dynamics.RESULTS:Among 209 patients with detectable FGFR2 expression, high-proportion FGFR2-IIIc (>0.28) was associated with significantly shorter overall survival compared with low-proportion FGFR2-IIIc (median 9.59 versus 16.0 months, hazard ratio 2.08, 95% confidence interval 1.33-3.26, P < 0.001). Multivariable Cox regression confirmed FGFR2-IIIc proportion as an independent predictor of poor prognosis (P = 0.008), superior to total FGFR2 expression levels. Longitudinal analysis of 33 paired pre- and post-treatment samples revealed treatment-induced increases in FGFR2-IIIc proportion (P = 0.0085), suggesting adaptive isoform switching. Notably, all tumors with elevated FGFR2 expression exclusively belonged to the low-IIIc group, indicating that current FGFR2-targeted therapies primarily benefit patients with FGFR2-IIIb-dominant expression profiles. High-proportion FGFR2-IIIc was significantly associated with epithelial-to-mesenchymal transition and myogenesis pathway activation. Differential splicing analysis identified coordinated alternative splicing events in ESRP1-regulated targets, suggesting potential broader splicing dysregulation and providing mechanistic insights into the aggressive phenotype.CONCLUSIONS:FGFR2-IIIc proportion represents a clinically relevant prognostic biomarker in advanced GC/GEJCs. Treatment-induced isoform switching toward FGFR2-IIIc suggests a novel resistance mechanism requiring targeted therapeutic approaches. These findings underscore the importance of developing isoform-specific therapeutic strategies and implementing FGFR2-IIIc assessment in precision oncology approaches for GC/GEJCs. |
| DOI | 10.1016/j.esmoop.2025.105851 |
| PMID | 41172570 |