Abstract 6199: Fusion genes: Novel therapeutic targets for gastric signet ring cell carcinoma
Authors: Wang Yue , Shi Tao , Wang Xuan , Hu Jinwei , Yu Lixia , Liu Qin , Wu Nandie , Liu Baorui , Wei Jia 
Published: June 2022

Abstract
Background: Gastric cancer (GC) is one of the most common lethal malignancies in the world. In recent years, clinicopathological characteristics of GC are changing, marked by increasing incidence of gastric signet ring cell carcinoma (GSRCC) histology. However, at present, no effective therapeutic targets for GSRCC. Fusion genes are considered as ideal therapeutic targets for various cancers with the development of sequencing technique. We attempted to target fusion genes to treat GSRCC.
Methods: We used STAR-Fusion, STAR-Seqr, Arriba to get fusion genes in 417 GC samples in The Cancer Genome Atlas (TCGA). Fusion genes identified simultaneously by at least two software are considered “real” fusion genes. Next, we included 556 GC samples of our specimen bank, including 64 GSRCC in this study. All histopathologic diagnoses were reviewed by at least two senior pathologists independently. Clinical information was retrospectively collected and the overall survival (OS) was measured from the date of surgery to the date of death or the last follow-up visit. Formalin fixed paraffin-embedded (FFPE) tissue were collected for next-generation sequencing (NGS) in a 450-gene panel assay.
Results: Among 417 GC samples in TCGA, we detected fusion genes in 283 (68%) samples. On average, each GC samples contained 7 fusion genes. And, a single sample contained a maximum of 85 fusion genes. We noticed that one GC sample had FGFR2-TACC2 fusion, which is recurrent and meaningful in intrahepatic cholangiocarcinoma and urothelium carcinoma. On the other hand, among 556 GC samples from our specimen bank, GSRCC patients had lower tumor mutation burden (TMB-L) (P=0.001) than non-SRCC patients. However, we detected gene fusions in 20.3% (13/64) GSRCC patients. GSRCC patients with gene fusions had a higher N stage (P=0.001) and a higher tumor stage (P=0.010) defined by 8th American Joint Committee on Cancer (AICC) criterion. Moreover, GSRCC patients harboring gene fusions (n=9) had poorer overall survival (OS) in comparison with patients without any gene fusion (n=19) (16.0 months vs 21.0 months, P=0.043). In addition, FGFR2 gene fusions (FGFR2-VTI1A and TACC2-FGFR2) were recurrently detected in 3.1% GSRCC tumor samples. We stably expressed TACC2-FGFR2 in gastric cancer cell lines. Using qRT-PCR, we found FGFR2 mRNA levels were increased in TACC2-FGFR2-expressing GC cells and IHC showed TACC2-FGFR2 upregulated FGFR2 protein expression in TACC2-FGFR2-expressing GC cells. Also, TACC2-FGFR2-expressing GC cells were more sensitive to FGFR2 inhibitors.
Conclusions: Our observation revealed that fusion genes were recurrent in GSRCC and might associate to shorter OS. FGFR2 fusion genes were recurrent in GSRCC and FGFR2 inhibitors might be a new therapeutic target for GSRCC.
Citation Format: Yue Wang, Tao Shi, Xuan Wang, Jinwei Hu, Lixia Yu, Qin Liu, Nandie Wu, Baorui Liu, Jia Wei. Fusion genes: Novel therapeutic targets for gastric signet ring cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6199.