Genomic Alterations in Biliary Tract Cancer Using Targeted Sequencing.
BACKGROUND
Biliary tract cancers (BTCs) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas. Patient-derived tumor cell (PDC) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs.


METHODS
Between January 2012 and June 2015, 40 BTC patients' samples were collected. PDCs were isolated and cultured from surgical specimens, biopsy tissues, or malignant effusions including ascites and pleural fluid. Genome analysis using targeted panel sequencing as well as digital multiplexed gene analysis was applied to PDCs as well as primary tumors.


RESULTS
Extrahepatic cholangiocarcinoma (N=15, 37.5%), intrahepatic cholangiocarcinoma (N=10, 25.0%), gallbladder cancer (N=14, 35.0%), and ampulla of Vater cancer (N=1, 2.5%) were included. We identified 15 mutations with diverse genetic alterations in 19 cases of BTC from primary tumor specimens. The most common molecular alterations were in TP53 (8/19, 42.1%), including missense mutations such as C242Y, E285K, G112S, P19T, R148T, R248Q, and R273L. We also detected two NRAS mutations (G12C and Q61L), two KRAS mutations (G12A and G12S), two ERBB2 mutations (V777L and pM774delinsMA) and amplification, and three PIK3CA mutations (N345K, E545K, and E521K). PDC models were successfully established in 27 of 40 samples (67.5%), including 22/24 from body fluids (91.7%) and 5/16 from tissue specimens (31.3%).


CONCLUSIONS
PDC models are promising tools for uncovering driver mutations and identifying rational therapeutic strategies in BTC. Application of this model is expected to inform clinical trials of drugs for molecular-based targeted therapy.
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Kwai Han
KH
Yoo
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
Nayoung K D
NK
Kim
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Woo Il
WI
Kwon
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
Chung
C
Lee
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Sun Young
SY
Kim
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jiryeon
J
Jang
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jungmi
J
Ahn
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Mihyun
M
Kang
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Hyojin
H
Jang
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Seung Tae
ST
Kim
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Soomin
S
Ahn
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Kee-Taek
KT
Jang
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Young Suk
YS
Park
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea.
Woong-Yang
WY
Park
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: jyunlee@skku.edu.
Jeeyun
J
Lee
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: jinseok.heo@samsung.com.
Jin Seok
JS
Heo
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: oncopark@skku.edu.
Joon Oh
JO
Park