Abstract 3156: Pathway Specific Functional Biomarkers for the Early Detection of Liver Cancer (2019)

Abstract In its early stages, HCC is curable; once advanced, HCC is associated with high mortality. HCC is associated with alterations in key driving pathways, including the Wnt pathway, TGF-β pathway, the p53 pathway, and pathways that regulate Myc activity. Members of the TGF-β superfamily regulate liver inflammation and can have tumor-suppressing or tumor-promoting activities that have been demonstrated to play key roles in liver and GI cancers through mouse models and human genomics. Yet, specific populations that are targetable with altered TGF-β remain unclear. Based upon our functional preclinical models and pilot studies in human liver disease samples, our hypothesis that aberrant expression of TGF-β pathways can lead to early detection of HCC and risk stratification. Methods and Results: Through preclinical studies that integrate analysis of human genomic data from The Cancer Genome Atlas (TCGA), mouse models, and human tissue/cell line studies, we sought to determine whether specific high-risk populations may be identified through a functional TGF-β pathway related biomarkers alterations. We observe the following: • Altered expression of TGF-β-Smad signaling genes is common in HCC (40%) • Somatic mutations in at least one gene encoding a member of the TGF-β-Smad pathway are common in HCC (38%) with the SMAD3 adaptor, β2SP (encoded by SPTBN1) having the highest frequency of mutation (6%), regardless of etiology, HBV or HCV infection or non-alcoholic steatohepatitis (NASH) • Disruption of the TGF-β-Smad pathway is associated with dysregulation of potentially targetable oncogenes that include MDM2, Telomerase, IGF2 and others. • TGF-β-Smad pathway activity clusters HCC patients into 4 groups. • HCC patients with a signature indicative of “inactivated” TGF-β-Smad signaling had shorter survival times than HCC patients with a signature indicative of “activated” TGF-β-Smad signaling reflecting a tumor suppressor role of TGF-β signaling in HCC. • TGF-β-Smad pathway activity correlates with genes in the DNA damage response and sirtuins. • Analysis of liver samples from normal subjects, patients with alcohol-induced cirrhosis, and alcohol-associated HCC showed that in the cirrhotic tissue TGF-β-Smad3 signaling and FANCD2 were highest and that in the HCC tissue these were lowest, suggesting a loss of this tumor-suppressing pathway in HCC • Mice deficient in either sirtuin activity (Sirt6-/-) or compromised TGF-β signaling (Sptbn+/-/Smad3+/-) are susceptible to liver injury, steatosis and spontaneously develop HCC • TGF-β-Smad pathway activity correlates with genes associated with hepatic fibrosis, immune cells, and the tumor microenvironment. Conclusions: Our data indicate that TGF-β-Smad members, particularly Smad3 and β2SP, and markers of DNA repair processes, particularly FANCD2 are potentially useful biomarkers of the loss from tumor-suppression by TGF-β signaling, which may be an early indicator of HCC. Citation Format: Kirti Shetty, Chu-Xia Deng, Wilma S. Jogunoori, Richard Amdur, Linda S. Resar, Patricia Latham, Raja Mazumder, Anelia Horvath, Bao-Ngoc Nguyen, Shulin Li, Xifeng Wu, Herbert Yu, Linda L. Wong, Jon White, Sylvia Silver, Asif Rashid, Vikas Kundra, Xin Wei Wang, Lopa Mishra. Pathway Specific Functional Biomarkers for the Early Detection of Liver Cancer [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 3156.