Abstract A041: Genetic landscape of intracholecystic papillary neoplasms (ICPNs) of the gallbladder - <i>STK11</i> as a characteristic driver gene for ICPNs-

Abstract Purpose: Intracholecystic papillary neoplasms (ICPNs) are papillary neoplastic formations of the gallbladder. Due to its variability in terminology and scarcity, clinicopathological and molecular research data on ICPNs has been in extreme shortage so far. In this study, we aimed to clarify the characteristics of ICPNs, and grasp their genetic landscape. Methods: Reevaluation and rediagonosis of all gall bladder tumor/polyp surgical specimen from two institutions was conducted, resulting in 35 cases of ICPNs. We studied the structural characteristics of ICPNs, and propose a previously nonexistent macroscopic classification of ICPNs. Immunohistochemical evaluation was conducted to examine the expression of major tumor suppressors. Next generation sequencing (NGS) was performed, and the data was analyzed by comparing them amongst dysplastic grades and morphologic phenotype, and detecting potentital driver genes, as well as comparing them with classic gallbladder carcinoma(GBC) database. Results: In order to gain insight on the macroscopic features of ICPNs, we propose that ICPNs be classified according to tumor base size in relation to tumor size, and the granular formations constituting the tumor surface. We identified morphologic subtypes by implementing immunohistochemistry and found that in multiple tumors harboring different dysplastic grades, a shift from gastric type to pancreato-biliary type was seen along with tumor progression. Immunohistochemical evaluation also showed that loss of expression of Serine/threonine kinase 11 (STK11) and nuclear expression of β-catenin were significantly more frequent in ICPNs compared to classic GBCs. We submitted 79 neoplastic samples and 47 matched normal samples for NGS. STK11, E74 like ETS transcription factor 3 (ELF3), and Catenin beta-1 (CTNNB1) were frequently altered across dysplastic grades and morphologic phenotypes. Statistical comparison with the classic GBC database showed that mutation rates of CTNNB1 and MYC were significantly higher in ICPNs. ELF3 and TP53 mutations were significantly lower in the low-grade components, suggesting that mutation of these genes may be associated with carcinogenesis of ICPNs. Using a gene mutation order algorithm, we discovered that frame shift mutations of STK11 occur before KRAS mutations, indicating that KRAS mutations occur later in tumorigenesis compared to other known gastrointestinal tumors. We also detected STK11 as a characteristic driver gene of ICPNs. Conclusion: Along with CTNNB1 and MYC mutations, STK11 mutation is a characteristic of ICPNs and may act as a driver gene. Our study suggests that gastric type ICPNs may shift to pancreato-biliary type along with tumor progression. Citation Format: Satomi Saito, Keigo Murakami, Taito Itoh, Yusuke Mizukami, Yusuke Ono, Yasunobu Okamura, Kengo Kinoshita, Michiaki Unno, Goro Honda, Toru Furukawa. Genetic landscape of intracholecystic papillary neoplasms (ICPNs) of the gallbladder -STK11 as a characteristic driver gene for ICPNs- [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A041.