Abstract 7499: Driver mutations propel subclonal evolution and spatial patterns of tumor growth in intrahepatic cholangiocarcinoma

Abstract Intrahepatic cholangiocarcinoma (ICC) is a highly lethal cancer of the bile ducts that exhibits a diversity of driver oncogenic mutations, several of which have been shown to be frequently subclonal. However, existing tumor evolution studies in ICC have been limited by either the number of sub-regions assessed or a paucity of driver mutation heterogeneity. Here, we conducted a multi-omic analysis of 90 tumor regions from 11 discrete tumors in 10 patients, identifying subclonal driver mutations in 5 of the patients, in the genes PBRM1, PIK3CA, TP53, ARID1A, BRAF, MLH1, and CDKN2A. This high-number multi-region approach also allowed us to unambiguously identify distinct subclonal evolutionary branches and map them to the spatial location of the samples. Importantly, each subclonal driver mutation was tightly associated with these defined branches, implicating them as a frequent mechanism of driving subclonal evolution. Additionally, subclonal branching showed a spatial correlation on surgical resection depicting the strength of multi-region sequencing in treatment. In total, we conclude that while subclonal branching can be driven by a number of factors, the acquisition of bona fide driver mutations strongly propels subclonal evolution and spatial patterns of tumor growth. Citation Format: Evit John, Pooja Shukla, Anish Jain, Alexandria Lau, Tom Lesluyes, Huw Ogilvie, Maxime Tarabichi, Jason Roszik, Yinyin Yuan, Peter Van Loo, Lawrence Kwong, Yun Shin Chun. Driver mutations propel subclonal evolution and spatial patterns of tumor growth in intrahepatic cholangiocarcinoma [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 7499.