Abstract 2150: <i>CLDN18/ARHGAP26</i> fusions in gastric cancers

Abstract Background Previous work has shown that young females, who present with genomically-stable, poorly-differentiated, diffuse gastric cancer harbor CLDN18/ARHGAP26 fusions more often than older individuals with intestinal type or non-diffuse gastric cancer histology. This fusion usually occurs between exon 5 of CLDN18 and exon 12 of ARHGAP26, is associated with a poor prognosis, and confers a propensity for metastasis. We investigated the prevalence of this fusion and characterized the fusion-positive patient population among gastric cancer patients whose tumor samples underwent OncoExtraTM assay testing. Methods Tumor and paired-normal samples from 171 gastric cancer patients aged 18-90 years were sequenced with the OncoExtraTM assay. This assay uses whole-exome DNA sequencing to detect somatic single base substitutions, indels, copy number alterations, and whole transcriptome RNA sequencing to detect gene fusions and alternative transcripts. The RNA sequencing data were used to identify CLDN18/ARHGAP26 fusions. Results The 171 patients were well balanced between sexes: 91 (53.2%) men, 80 (46.8%) women. Most patients were older: 44 (25.7%) ≤50 years old, 127 (74.3%) &amp;gt;50 years old. There were 6 (3.5%) patient samples with a CLDN18/ARHGAP26 fusion. The fusion was found more often in females (5 of 80, 6.3%) than males (1 of 91, 1.1%) and younger patients (3 of 44, 6.8%, ≤50 years; 3 of 127, 2.3%, &amp;gt;50 years). All 6 had diffuse histology by pathology, variably described as poorly differentiated, diffuse, or signet ring subtype. Notably, the 2 patients with mixed histology did not have metastases reported on the pathology report, while the 4 whose histology was described as diffuse or signet ring cell type were metastatic. In all cases the fusion involved exon 5 of CLDN18 and exon 12 of ARHGAP26. Further analysis revealed that five of the fusion-containing tumors had alterations in genes/pathways known to be oncogenic drivers of cell proliferation, specifically 1 ERBB2 (2 mutations present), 1 SWI/SNF pathway (ARID1A and PBRM1 both altered), 2 MET (both amplifications), and 1 PI3K pathway (PI3KCA altered). The sixth tumor sample possessed no obvious driver alterations: only TP53 and WRN were altered. Five of the 6 tumors had low tumor mutational burden (TMB) and were microsatellite stable, the sixth had intermediate TMB, and none had evidence for genomic instability. No CLDN18 fusions were found in any other solid tumors (7050 samples). Conclusions The OncoExtraTM assay detected gastric cancer CLDN18/ARHGAP26 fusions at a frequency (3.5%) similar to previous reports. The majority were female and of younger age compared to patients lacking this fusion. Five of the 6 tumors had additional oncogenic alterations associated with cell proliferation. Given its frequency in poorly differentiated gastric cancer with metastatic potential, as well as its prevalence in a relatively young cohort, this fusion is an attractive target for ongoing drug development. Citation Format: Deborah Josefson, David W. Hall, Jess Hoag, Ariane Kemkes, Janine LoBello, Snehal G. Thakkar, Gargi Basu. CLDN18/ARHGAP26 fusions in gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2150.