Shunichi Tsuge1, Behnam Saberi1,2, Yulan Cheng1, Zhixiong Wang1,3, Amy Kim1, Harry Luu1, John M Abraham1, Maria D Ybanez4, James P Hamilton1, Florin M Selaru1, Carlos Villacorta-Martin2, Felix Schlesinger5, Benjamin Philosophe6, Andrew M Cameron6, Qingfeng Zhu7, Robert Anders7, Ahmet Gurakar1, Stephen J Meltzer1,4,8. 1. Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 2. Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA. 3. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 4. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 5. Illumina, San Diego, California, USA. 6. Department of Transplant Surgery, The Johns Hopkins University, Baltimore, Maryland, USA. 7. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 8. Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is now the second-highest cause of cancer death worldwide. Recent studies have discovered a wide range of somatic mutations in HCC. These mutations involve various vital signaling pathways such as: Wnt/β-Catenin, p53, telome-rase reverse transcriptase (TERT), chromatin remodeling, RAS/MAPK signaling, and oxidative stress. However, fusion transcripts have not been broadly explored in HCC. METHODS: To identify novel fusion transcripts in HCC, in the first phase of our study, we performed targeted RNA sequencing (in HCC and paired non-HCC tissues) on 6 patients with a diagnosis of HCC undergoing liver transplantation. RESULTS: As a result of these studies, we discovered the novel fusion transcript, VTI1A-CFAP46. In the second phase of our study, we measured the expression of wild-type VTI1A in 21 HCC specimens, which showed that 10 of 21 exhibited upregulation of wild-type VTI1A in their tumors. VTI1A (Vesicle Transport via Interaction with t-SNARE homolog 1A) is a member of the Soluble N-ethylmaleimide-Sensitive Factor (NSF) attachment protein receptor (SNARE) gene family, which is essential for membrane trafficking and function in endocytosis, autophagy, and Golgi transport. Notably, it is known that autophagy is involved in HCC. CONCLUSIONS: The link between novel fusion transcript VTI1A-CFAP46 and autophagy as a potential therapeutic target in HCC patients deserves further investigation. Moreover, this study shows that fusion transcripts are worthy of additional exploration in HCC.
BACKGROUND: Hepatocellular carcinoma (HCC) is now the second-highest cause of cancer death worldwide. Recent studies have discovered a wide range of somatic mutations in HCC. These mutations involve various vital signaling pathways such as: Wnt/β-Catenin, p53, telome-rase reverse transcriptase (TERT), chromatin remodeling, RAS/MAPK signaling, and oxidative stress. However, fusion transcripts have not been broadly explored in HCC. METHODS: To identify novel fusion transcripts in HCC, in the first phase of our study, we performed targeted RNA sequencing (in HCC and paired non-HCC tissues) on 6 patients with a diagnosis of HCC undergoing liver transplantation. RESULTS: As a result of these studies, we discovered the novel fusion transcript, VTI1A-CFAP46. In the second phase of our study, we measured the expression of wild-type VTI1A in 21 HCC specimens, which showed that 10 of 21 exhibited upregulation of wild-type VTI1A in their tumors. VTI1A (Vesicle Transport via Interaction with t-SNARE homolog 1A) is a member of the Soluble N-ethylmaleimide-Sensitive Factor (NSF) attachment protein receptor (SNARE) gene family, which is essential for membrane trafficking and function in endocytosis, autophagy, and Golgi transport. Notably, it is known that autophagy is involved in HCC. CONCLUSIONS: The link between novel fusion transcript VTI1A-CFAP46 and autophagy as a potential therapeutic target in HCC patients deserves further investigation. Moreover, this study shows that fusion transcripts are worthy of additional exploration in HCC.
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Authors: Philip J Stephens; David J McBride; Meng-Lay Lin; Ignacio Varela; Erin D Pleasance; Jared T Simpson; Lucy A Stebbings; Catherine Leroy; Sarah Edkins; Laura J Mudie; Chris D Greenman; Mingming Jia; Calli Latimer; Jon W Teague; King Wai Lau; John Burton; Michael A Quail; Harold Swerdlow; Carol Churcher; Rachael Natrajan; Anieta M Sieuwerts; John W M Martens; Daniel P Silver; Anita Langerød; Hege E G Russnes; John A Foekens; Jorge S Reis-Filho; Laura van 't Veer; Andrea L Richardson; Anne-Lise Børresen-Dale; Peter J Campbell; P Andrew Futreal; Michael R Stratton Journal: Nature Date: 2009-12-24 Impact factor: 49.962