Abstract 3431: Evaluation of genetic mutations and copy number alterations in biliary tract cancer using targeted exome sequencing
Authors: Chae Heejung , Yoo Changhoon , Kim Deokhoon , Lee Seonmin , Bi Kim Dan , Jeong Jae Ho , Chang Heung-Moon , Ryoo Baek-Yeol , Kim Kyu-pyo 
Published: August 2018

Abstract
Background: Biliary tract cancer (BTC) is a heterogeneous group of cancers anatomically divided into the gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). None of molecular target agents has been proven to improve the prognosis of BTC yet. To gain a deeper understanding of BTC's pathophysiology and find its new potential therapeutic targets, this study is aimed to investigate genetic profiles of BTC and their clinical implications.
Methods: A total of 69 patients who had been pathologically diagnosed as adenocarcinoma of biliary tract from January 2014 to November 2016 and had available surgical or biopsy specimen were enrolled for this study. With the DNA specimen extracted from previously-collected tumor tissue, somatic mutations and copy number variation (CNV) analyses were performed using targeted exome sequencing. Data regarding the baseline patient characteristics and treatment outcomes were retrospectively obtained by reviewing the patients' medical records.
Results: Nineteen patients with GBC (28%), 24 patients with ICC (35%) and 26 patients with ECC (37%) were included in this analysis. Genetic mutation and copy number alteration (CAN) were observed in 59 (85%) and 35 (51%) patients, respectively while 5 patients (7%) did not have any genetic alterations. The most commonly mutated gene was TP53 (n=33, 47.8%), followed by KRAS (n=18, 26.1%), ARID1A (n=10, 14.5%) and IDH1 (n=9, 13.0%). IDH1 mutation appeared more frequently in patients with ICC (n=7, 29.2%, P=0.015) compared to those with GBC (n=1, 5.3%) or ECC (n=1, 3.8%) while ERBB2 and ERBB3 mutation were found only in GBC and ECC. HER2 amplification was observed in 7 patients (4 with GBC and 3 with ICC). Among those, one patient showed 3+ for HER2 test by immunohistochemistry (IHC) while four patients were 2+. All somatic mutations and CNVs documented in the present study were classified into five pathway modules which were identified by Nakamura et al. (Nature Genetics 2015). Majority of genetic alterations (n=45, 65.2%) belonged to Kinase-RAS module, followed by TP53 (n=41, 59.4%), TGF-β-SWI/SNF-MYC (n=22, 31.9%), Epigenetic (n=16, 23.2%) and RB-cell cycle (n=10, 14.5%) modules. Alterations in Epigenetic module were most common in ICC (vs. GB vs. ECC, 50.0% vs. 15.8% vs. 3.8%, P=0.002) while alterations in TGF-β-SWI/SNF-MYC module were most frequent in ECC (vs. GB vs. ICC, 46.2% vs. 3.6% vs. 31.6%, P=0.031).
Conclusion: Genetic profile of BTC is heterogeneous according to its anatomic location. Our results indicate that subgroup of BTC patients may have benefit from targeted therapy such anti-IDH and anti-HER2 inhibitors.
Citation Format: Heejung Chae, Changhoon Yoo, Deokhoon Kim, Seonmin Lee, Kim Dan Bi, Jae Ho Jeong, Heung-Moon Chang, Baek-Yeol Ryoo, Kyu-pyo Kim. Evaluation of genetic mutations and copy number alterations in biliary tract cancer using targeted exome sequencing [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 3431.