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Cholangiocarcinoma is a devastating malignancy with fatal complications that exhibits low response and resistance to chemotherapy. Here, we evaluated the anticancer effects of CG200745, a novel histone deacetylase inhibitor, either alone or in combination with standard chemotherapy drugs in cholangiocarcinoma cells. CG200745 dose-dependently reduced the viability of cholangiocarcinoma cells in vitro and decreased tumour volume and weight in a xenograft model. Administering CG200745 along with other chemotherapeutic agents including gemcitabine, 5-fluorouracil (5-FU), cisplatin, oxaliplatin, or gemcitabine plus cisplatin further decreased cholangiocarcinoma cell viability, with a combination index in vitro and in vivo, and acts synergistically when administered in combination with standard chemotherapeutic agents, enabling dose reduction. CG200745 is therefore expected to improve the outcome of cholangiocarcinoma patients who exhibit resistance to conventional therapies.

Background: Gene fusion occurs when a part of one gene fuses with a part of another gene by genome rearrangement and may possess oncogenic properties. Bile duct cancer (BDC) are one of the most lethal malignancy, but lack of proper diagnostic or prognostic markers. Our aim was to investigate BDC specific fusion genes found in patient's specimens and its clinical significance. Method : We extracted total RNA from five BDC tissues and normal tissues from the same patients. RNA sequencing was performed and the result data was analyzed using ChimeraScan, Jaffa or FusionCatcher softwares to detect gene fusion. The expression of the detected novel fusion gene was confirmed by ddPCR using tissues from the operated BDC patients and its clinical significance was analyzed with medical information of the patients. Result : We found 52 BDC specific fusion genes by RNA sequencing and we identified novel BDC specific fusion gene, PUM1-TRAF3 by bioinformatics analysis. Total 55 patients with BDC who underwent curative surgery were evaluated to investigate clinical significance of PUM1-TRAF3. There were 28 patients (50.1%) who expressed PUM1-TRAF3 by ddPCR. Patients with PUM1-TRAF3 presented higher rate of female gender (57.1 vs. 25.9, p=0.019), advanced stage (25% vs. 3.7%, p=0.025) and recurrence rate (64.7 vs. 48.1%, p=0.080) compared to patients without PUM1-TRAF3. Disease free survival (DFS) was 12.1 vs. 29.8 (p=0.078) and overall survival was 26.1 vs. 36.6 (p=0.239) between the patients with PUM1-TRAF3 and without PUM1-TRAF3. In multivariated analysis by cox-regression, expression of PUM1-TRAF3 (HR 2.86, p=0.023), advanced stage (HR 2.69, p=0.041), higher CA19-9 (HR 1.00, p=0.011) and positive resection margin (HR 4.57, p=0.002) were significantly associated with short DFS.Conclusion : In this study, we identified novel BDC-specific fusion gene, PUM1-TRAF3. Expression of PUM1-TRAF3 was confirmed in patient's tissues and associated with short DFS in operated BDC patients. PUM1-TRAF3 can be a potent biomarker in BDC. Citation Format: Dawoon E. Jung, Kahee Kim, Chanyang Kim, Soo Been Park, Jung Hyun Jo, Hee Seung Lee, Si Young Song. Identification of novel fusion gene, PUM1-TRAF3, as potent biomarker in bile duct cancer [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 4337.

Gene fusion occurs when a part of one gene fuses with or attaches to a part of another gene by genome rearrangement and the result in gene fusion may possess oncogenic properties; fused gene may be translated into a unique protein that may promotes cancer properties. Bile duct cancer are one of the most lethal cancer types with low 5-year survival rates, but lack of proper diagnostic or prognostic markers. Our aim was to investigate bile duct cancer specific fusion genes found in patient’s specimens. We extracted total RNA from five bile duct cancer tissues and normal tissues from the same patients. We performed RNA sequencing and the result data was analyzed using ChimeraScan, Jaffa or Fusionchacher softwares to detect gene fusion. To identify the cancer somatic fusion gene, the fusion occurred in normal tissues and previously reported fusion genes found in normal tissues were excluded and the fusion occurred in coding region was included. As a result, we found 52 bile duct cancer tissue specific- fusion genes. We analyzed the expression of selected fusion genes in 30 bile duct cancer patients and cancer cell lines by qRT-PCR. As a result we observed two novel bile duct cancer specific fusion genes. We cloned one of the fusion genes and transfected into the bile duct cancer cell lines SNU-1196 to assess, and increase in cell motility was observed in vitro. These findings indicate the presence of novel fusion genes as well as its possible application for the early diagnosis or prognosis of bile duct cancer. Citation Format: Kahee Kim, Dawoon Esther Jung, Mi-kyoung Seo, Sang Woo Kim, Si Young Song. Identification of bile duct cancer specific fusion genes in patient tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4398. doi:10.1158/1538-7445.AM2017-4398

Gene fusion occurs when a part of one gene fuses with or attaches to a part of another gene by genome rearrangement and the result in gene fusion may possess oncogenic properties; fused gene may be translated into a unique protein that may promotes cancer properties. Pancreatic cancer and bile duct cancer are one of the most lethal cancer types with low 5-year survival rates, but lack of proper diagnostic or prognostic markers. Our aim was to investigate pancreatobilliary- specific fusion genes found in patient's specimens. We used TRIzol to extract total RNA from seven pancreatic cancer tissues and normal tissues from the same patients, and five bile duct cancer tissues and normal tissues from the same patients. Total RNA was assessed for RNA sequencing and the result data was analyzed using ChimeraScan to detect gene fusion. To identify the cancer somatic fusion gene, the fusion occurred in normal tissues and previously reported fusion genes found in normal tissues were excluded and the fusion occurred in coding region was included. As a result, we found 87 pancreatic cancer tissue specific- and 52 bile duct cancer tissue specific- fusion genes. We then selected fusion genes that either one of the gene has been reported to express in cancer tissues. We confirmed the expression of selected fusion genes by RT-PCR in cancer and normal tissues as well as in cancer cell lines. As a result we observed novel pancreatobilliary cancer specific fusion genes. These findings indicate the presence of novel fusion genes as well as its possible application for the early diagnosis or prognosis of pancreatic and bile duct cancer. Citation Format: Kahee Kim, Dawoon E. Jung, Mi-kyoung Seo, Sang Woo Kim, Si Young Song. Identification of pancreatobilliary cancer specific fusion genes in patient tissues. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 101.