Akbanni, Rehan

Chen, Jian

Deng, Chuxia

gu, shoujun

Horvath, Anelia

Jogunoori, Wilma S

Li, Shulin

Mazumder, Raja

Mishra, Bibhuti

Mishra, Lopa

Network, The TCGA Cancer

Ohshiro, Kazufumi

Pattabiraman, Nagarajan

RAO, SHUYUN

White, Jon

Wu, Ray-Chang

Zaidi, Sobia

English

VCU Scholars Compass

Virginia Commonwealth UniversityVCU Scholars CompassHepatobiliary Cancers: Pathobiology andTranslational Advances Dept. of Pathology2017Hepatocellular Cancer Genome andTranscriptome Analysis Validates ClinicallySignificant Mutational Signatures with the TGF-?PathwaySHUYUN RAOraoshuyun@gwu.eduJian ChenThe University of Texas MD Anderson Cancer Center, jianchen@mdanderson.orgKazufumi OhshiroGeorge Washington University - School of Medicine and Health Sciences, kazufumiohshiro@gmail.comSee next page for additional authorsFollow this and additional works at: http://scholarscompass.vcu.edu/hepa_cancersPart of the Integrative Biology Commons, Medical Molecular Biology Commons, and theMolecular Genetics Commons© The Author(s)This Abstract Accepted for Presentation is brought to you for free and open access by the Dept. of Pathology at VCU Scholars Compass. It has beenaccepted for inclusion in Hepatobiliary Cancers: Pathobiology and Translational Advances by an authorized administrator of VCU Scholars Compass.For more information, please contact libcompass@vcu.edu.Downloaded fromhttp://scholarscompass.vcu.edu/hepa_cancers/15AuthorsSHUYUN RAO, Jian Chen, Kazufumi Ohshiro, shoujun gu, Sobia Zaidi, Wilma S. Jogunoori, Jon White,Nagarajan Pattabiraman, Raja Mazumder, Anelia Horvath, Ray-Chang Wu, Shulin Li, Chuxia Deng, BibhutiMishra, Rehan Akbanni, The TCGA Cancer Network, and Lopa MishraThis abstract accepted for presentation is available at VCU Scholars Compass: http://scholarscompass.vcu.edu/hepa_cancers/15Hepatocellular Cancer Genome and Transcriptome Analysis Validates Clinically Significant Mutational Signatures with the TGF-𝛃 Pathway Shuyun Rao1, Jian Chen2, Kazufumi Ohshiro1, Shoujun Gu1, Sobia Zaidi1, Wilma S. Jogunoori3, Jon White3, Nagarajan Pattabiraman4, Raja Mazumder4, Anelia Horvath4, Ray-Chang Wu5, Shulin Li6, Chu-Xia Deng1,7, Bibhuti Mishra1, Rehan Akbani8, The TCGA Cancer Network, Lopa Mishra1,3,*  1Center for Translational Research, Department of Surgery, George Washington University, Washington DC, USA; 2Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Surgical Service, Veterans Affairs Medical Center, Washington, DC, USA; 4Department of Biochemistry and Molecular Medicine, McCormick Genomic and Proteomic Center, George Washington University, Washington, DC, USA; 5Department of Biochemistry and Molecular Biology, George Washington University, Washington, DC, USA; 6Departments of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA;  7Faculty of Health Sciences, University of Macau, Macau SAR, China; 8Departments of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA *corresponding author  Development of hepatocellular carcinoma (HCC) is associated with alterations in the TGF-β signaling pathway, which regulates liver inflammation and can have tumor suppressor as well as promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. We performed transcriptome analyses for 488 human HCCs that include TCGA data to identify and validate the effects of this pathway in HCC and identify potential therapeutic targets. Our data reveals that decreased levels of TGF-β–related genes, associated with loss of TGF-β tumor suppressor function and a significantly poorer survival as compared to the group with increased levels of TGF-β related genes (P=.0129). About 38% of HCC samples showed somatic mutations in at least one of the TGF-β members. These alterations correlate with DNA repair genes such as FancD2 but irrespective of known risk factors such as HBV, HCV and alcohol. SPTBN1, a Smad3 adaptor, was mutated in the largest proportion of samples (12/202, 6%). Further functional validation identified a loss of function mutation of SPTBN1-D1089Y, which leads to decreased FancD2 levels and increased sensitivity to DNA crosslinking agents. Interestingly, we also observed strong correlations between the inactivated TGF-β signature and deregulation of Sirtuin pathways. Additional analysis of Sirtuins in TGF-β deficient cells revealed positive feedback regulation of Sirtuins by TGF-β.  Loss of TGF-β signaling inhibits Sirt1 and Sirt6 expression and vice versa.  Overall, our findings provide new insight into how disruption of the TGF-β pathway correlates with deregulation of DNA repair pathway and Sirtuins, which lead to increased genomic instability, epigenetic changes and thereby promotes liver cancer progression. 

Hepatocellular Cancer Genome and Transcriptome Analysis Validates Clinically Significant Mutational Signatures with the TGF- Pathway

https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=1023&context=hepa_cancers

Hepatocellular Cancer Genome and Transcriptome Analysis Validates Clinically Significant Mutational Signatures with the TGF- Pathway

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