Abstract 4351: Intratumoral heterogeneity and process of evolution of intrahepatic cholangiocarcinoma
Authors: Kitagaw Akihiro , Komatsu Hisateru , Kuroda Yosuke , Ito Syuhei , Masuda Takaaki , Eguchi Hidetoshi , Eguchi Hidetoshi , Doki Yuichiro , Mori Masaki , Mimori Koshi 
Published: August 2018

Abstract
Background: Intrahepatic cholangiocarcinoma(ICC) accounts for about 10% of all primary liver cancer. South Asia and a part of Chile, but in recent years it has been increasing in other areas including Europe and the United States. The only potentially curative treatment for patients who have a resectable tumor is surgery. Unfortunately, even after curative-intent surgery, the clinical outcomes of patients undergoing liver resection are disappointing, with a 5-year survival rate of 20% to 35%. Furthermore, the role of the other treatments, including systemic chemotherapy and radiotherapy, remain poorly defined and have been reported to have a favorable therapeutic effect. In this study, we reveals the intratumoral heterogeneity and process of evolution of intractable ICC without fully genomic understanding.
Material and method: Surgical specimens of 10 patients with resection of ICC in curative intention were acquired between 10/2014 and 5/2016. The average tumor size was 47 mm(range 30-80 mm). We obtained 57 samples at 3-9 lesions for each case, and performed whole exome sequencing using the next generation sequencer (HiSeq2500). Multiregional analysis was performed respectively on these cases, and we investigated intratumoral heterogeneity of ICC. Furthermore, we guessed the process of clonal evolution of ICC from the result of whole exome sequencing.
Result: We defined "Founder mutation" as only a mutation present in all samples in each case , and defined “Progressor mutation” as several mutations present in some samples in each case. Furthermore, we classified “Progressor mutation” as “Shared mutation” present in several samples in each case but not all and “Unique mutation” present in one sample in each case). In 10 cases, mean number of Founder, Unique and Shared mutation were 53%(range 24-74%), 18%(range 5-40%), and 29%(range 6-54%), respectively, and this indicated intratumoral heterogeneity in ICC. In addition, Founder mutation mainly including TP53, SMAD4, and NRAS were common in 2 cases, but no common Founder mutation was observed in over 3 cases, so this indicated intratumoral heterogeneity in ICC. This results leaded to the process of clonal evolution during tumor formation, describing the evolutionary trees.
Conclusion: In this study, multiregional analysis was performed on samples of ICC, and intratumoral heterogeneity and the process of clonal evolution were evaluated. This result confirms the resistance to current treatment and it seems that it is necessary to search for further therapeutic targets.
Citation Format: Akihiro Kitagaw, Hisateru Komatsu, Yosuke Kuroda, Syuhei Ito, Takaaki Masuda, Hidetoshi Eguchi, Hidetoshi Eguchi, Yuichiro Doki, Masaki Mori, Koshi Mimori. Intratumoral heterogeneity and process of evolution of intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4351.