Abstract 3401: Genomic and transcriptome profile of 66 Chinese biliary tract cancer patient derived cell lines

Abstract

Background: Biliary tract cancer (BTC) is an aggressive cancer with very poor prognosis. Currently there is no effective target therapy for BTC. To understand the genetic basis and look for potential drug targets of BTC, we sequenced the whole exome and transcriptome of 66 patient-derived primary cancer cells (PDC) from 23 unique patient samples. Methods: We cultured 66 patient derived cell lines (PDC) passage range from P10 to P15, from 23 BTC patients, with 1-9 PDC each patient. Both genomic DNA and total RNA were extracted from these cell lines, followed by WES and RNA sequencing on NovaSeq and HiSeq, respectively. Average sequencing coverage for WES is 139X and average data amount for RNA is 8.4Gbp. Variant calling was done by union set of Mutect and Pindel, with VAF cut-off 0.1 and filtered with a white variant list from COSMIC database. CNV was called from WES data by CNVKit with log2ratio cut-off 1.2. RNASeq data was mapped by STAR and fusion was calling by STAR-Fusion with at least 3 split reads. Results: A median of 57 non-silent mutations were identified in Chinese BTC which was about 2 folds (57 vs. 30) of that in TCGA cholangiocarcinoma. Ethnic differences were found between Chinese and western population. The top four genes with frequency in Chinese BTC higher than TCGA cholangiocarcinoma were TP53 (56.5% vs. 14.3%), EPPK1 (26.1% vs. 2.9%), FRAS1 (13.0% vs. 2.9%), and ZFHX3 (13.0% vs. 2.9%), while ANKRD36C (4.4% vs. 20.0%), PBRM1 (8.7% vs. 22.9%), and TCHH (4.4% vs. 17.1%) were the top three genes with frequency lower than TCGA cholangiocarcinoma. We also found two previously reported cholangiocarcinoma related genes, PEG3 and GNAS, both harbored mutations in 3 of 23 patients (8.7%) in our data. However, they were not reported in TCGA cholangiocarcinoma. A median of 158 CNVs (range: 5-299) in gene level were identified, and the top three frequently mutated CNVs genes were LILRA3, SIRPB1, and GSTT1. Copy number loss of CDKN2A were found in 7 of 23 patients. Totally, 234 unique fusions were identified with 2-17 fusions per patient (median: 8). Among these fusions 5 of them (C15orf57-CBX3, SCARB1-UBC, SAMD5-SASH1, NCOR2-UBC, and FTH1-EIF5A) were reported to be associated with cancers. There were also 19 fusions found in TCGA pan-cancer datasets. Conclusions: We built a comprehensive mutation landscape for Chinese BTC patients. Our results demonstrated ethnic differences between Chinese and TCGA Western cholangiocarcinoma patients. These PDC samples with profiled genetic information are good in vitro models for drug target discovery and validation for BTC patients. Citation Format: Feiling Feng, Qingbao Cheng, Bin Li, Liang Yang, Hua Dong, Bin Li, Dadong Zhang, Chang Xu, Xiaoya Xu, Yong Yu, Zishuo Chen, Zhizhen Li, Fugen Li, Zhiquan Qiu, Chen Liu, Xiaoqing Jiang. Genomic and transcriptome profile of 66 Chinese biliary tract cancer patient derived cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3401.