Background: TGF-β plays a complex role in cancer- from tumor suppression to immune modulation to tumor promotion that are unclearly defined to date. Recent clinical studies show that targeting TGF-β improves survival up to 21 months, yet prognostic significances are undefined. Moreover, the relationships between patterns of mutations and transcriptomic phenotypes for the TGF-β pathway are unclear. Methods: 1. We analyzed the transcriptome of 488 hepatocellular cancers and screened for mutations in the TGF-b pathway in 202 HCCs from The Cancer Genome Atlas (TCGA). 2. Next we correlated mouse models of HCC with a functional analysis of drivers. Results: 1. Transcriptomic analyses revealed aberrant TGF-β superfamily profiles in 72% of hepatocellular cancers, with mutations in 38% of patients. 2. Significantly, HCCs characterized by the “inactivated” TGF-β signature were associated with a significantly poorer survival particularly in early stage HCCs, compared to HCCs with the “activated” TGF-β signature (p = 0.0027). 3. We observed the greatest number of functional mutations in the SPTBN1 gene (6%), which encodes a tumor suppressor TGF-β/Smad3 adaptor protein. 4. We found a strong association between DNA damage response genes and the TGF-β pathway at both transcriptomic and genomic levels. 5. We also observed a strong correlation between VD related genes and TGF-β pathway genes in the TCGA genomic analysis. 6. subsequent VD deprivation synergistically with TGF-β inactivation promotes liver tumor development. 7. Through a transcriptomic and functional analysis we observed that TLR7 mRNA levels are increased 4-fold in liver tissues from Smad3+/- mice, and TLR7 is a direct target of Smad3. Conclusions: The TGF-β pathway plays a pivotal role in liver tumorigenesis and the molecular signatures we characterize here have prognostic significance. In specific populations, VD deficiency and TGF-β disruption synergistically promote liver tumor growth, possibly through regulating TLR7 expression. The additional association with the DNA repair pathway supports new approaches to biomarker driven targeting of TGF-β, improving survival of liver cancer.
Citation Format: Jian Chen, Jiun-Sheng Chen, Jianping Zhang, YoungJin Gi, Lior Katz, Ji-Hyun Shin, YunSeong Jeong, Mitch Belkin, Wilma Jogunoori, Bibhuti Mishra, Jon White, Shoujun Gu, Milind Javle, Xiaoping Su, John Stroehlein, Marta Davila, Xuemei Wang, Jeffrey Morris, Patrizia Farci, Rehan Akbani, Lopa Mishra. Comprehensive study of TGF-β pathway-driven functional molecular characterization of human hepatocellular cancer. [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 4425.