Abstract 1474: Recurrent PRKCI gene fusions represent a drug target in gastric cancer and esophageal junction cancer

Abstract Background: Protein kinase C (PKC) is a phospholipid-dependent, calcium-independent Ser/Thr protein kinase family with eight members, each involved in processes including apoptosis, migration, and proliferation. PRKCI promotes tumor growth in many types of cancer, including pancreatic, lung, ovarian, and renal cell carcinoma. Structurally, PKCι has an N-terminal regulatory domain and a C-terminal catalytic domain. While PRKCI fusions have been reported, they remain uncharacterized. This study aims to investigate these fusions in gastric cancer and esophageal junction carcinoma, exploring potential mechanisms and co-occurring mutations to inform targeted therapies that could improve patient outcomes. Methods: We performed a comprehensive analysis of PRKCI fusions identified from whole transcriptome sequencing (WTS) and associated co-occurring pathogenic mutations from whole exome sequencing (WES). We screened 6437 EJC and 3615 gastric adenocarcinoma cancer cases retrospectively and calculated the frequency of occurrence of PRKCI fusions. Additionally, we characterized and mapped the domains of PRKCI fusions and its partners. We further analyzed patient demographics, co-occurring mutations and copy number amplifications. Results: PRKCI fusions were identified in 0.19% and 0.3% of EEJC and Gastric adenocarcinoma cancer cases. All the PRKCI fusions are formed with other genes on chromosome 3 from intra-chromosomal rearrangement (PHC3, TNIK, SKIL and YES1) proximal to the PRKCI gene. The most common fusions of PRKCI are formed with partner PHC3 and SKIL which account for 11 patient cases. This is followed by 4 cases of TNIK and unique cases of fusions with LRRC31, PCYT1A, ERBB2, VPS13D and YES. Further, the genomic landscape of PRKCI indicated co-occurring mutations in TP53 (46.7%), ARID1A (13.3%), 6.7% inactivating mutations of ATM, FBXW7, CDH1. Expression of PRKCI in PRKCI fusion positive cases was significantly higher as opposed to patient cases that did not harbor gene fusions. PRKCI fusion cases were commonly observed to have PRKCI amplification (46.7%). PRKCI fusions lack the regulatory domain, leading to constitutive kinase activation, which may drive tumor progression by disrupting normal regulation and altering protein localization. Conclusion: Our studies are the first to identify PRKCI fusions in gastric cancer and EEJC patients, along with associated mutations and amplifications suggesting a novel mechanism. This highlights the importance of personalized molecular diagnostics to guide tailored treatments. PKCι kinase inhibitors may improve survival and outcomes for patients with PRKCI fusions in gastric cancer and EEJC. Citation Format: Shivani Jagannathan Murali, Bharath Kumar Karre, Cristina Ivan, Chao Sima, Asfetaw Abera, David Spetzler, Milan Radovich, Heather O'neill, Ravi Chakra Turaga. Recurrent PRKCI gene fusions represent a drug target in gastric cancer and esophageal junction cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1474.