Abstract 3382: A pan-cancer analysis reveals high frequency genetic alterations in mediators of signaling by the TGF-β superfamily
Authors: Ohshiro Kazufumi , Zaidi Sobia , Korkut Anil , Chen Jian , Rao Shuyun , Gu Shoujun , Jogunoori Wilma , Mishra Bibhuti , Akbani Rehan , Mishra Lopa 
Published: August 2019

Background: TGF-β/SMAD signaling is a crucial, often contradictory regulator in multiple stages of liver disease that include inflammation, cirrhosis and development of HCC as well as other cancers. The context-specific role of this pathway in treatment strategies has yet to be clarified. Therefore, understanding the multiple context-specific roles of the pathway across broad cancer types is critical towards deciphering the complexities of the pathway.

Methods: We followed our previous analysis of HCCs, by extending and examining TGF-β pathway across 33 TCGA tumor types and 9125 samples to address this question. We focused on 43 core genes that encode components that regulate signaling by the TGF-β superfamily with 50 target genes collectively identified through a consensus among TCGA network members. In addition, we extended our analyses to functional studies in mouse mutants and human cell lines with alterations of TGF-β signaling.

Results: Focusing on 43 core TGF-β pathway genes, we found at least one of them was genomically altered in 39% of samples (mutations: 24%, homozygous deletions: 10%, or amplifications: 14%). We observed the highest alteration frequencies with hotspot mutations, 65% of which were in liver and GI cancers. We identified hotspots in 6 genes, with new discoveries in TGFBR2 and BMP5. Interestingly, with all 6 hotspot mutations we observed increased expression of TERT, HMGA2, IL6, MMP9, COL1A1/1A2/3A1, MYC, and FOXP3. Surprisingly, CDH2, and ALDH1A1expression levels were markedly reduced in liver and GI cancers. Alterations in the core genes correlated positively with expression of metastasis-associated genes, and poor patient survival. Epigenetic silencing and miRNA expression were associated with limited activity of the pathway in a cancer dependent manner. Using proteomics data, elevated TGF-β pathway activity showed positive correlation activity of DNA damage repair and EMT pathways (R=0.24, p &lt; 0.0001), while the cell cycle and apoptosis pathways showed strong negative correlation (R= -0.3, and -0.15, p &lt; 0.0001). Functional analyses reveal that disruption of TGF-β leads to increased sensitivity to cisplatin and other DNA cross linking agents as well as radiation.

Conclusions: Our data suggest that TGF-β superfamily indices when combined with specific genes, such as HMGA2 and TERT, may represent strong prognostic markers, and targets in some cancer types such as HCC. This study provides a rich resource and broad molecular perspective that could guide future functional and therapeutic studies of the diverse set of cancer pathways mediated by TGF-β superfamily. In addition, when the pathway is disrupted, epithelial cells are more susceptible to transformation and invasion, potentially identifying specific populations that are more sensitive to chemotherapy such as cisplatin and 5FU, as well as radiation therapy.

Citation Format: Kazufumi Ohshiro, Sobia Zaidi, Anil Korkut, Jian Chen, Shuyun Rao, Shoujun Gu, Wilma Jogunoori, Bibhuti Mishra, Rehan Akbani, Lopa Mishra. A pan-cancer analysis reveals high frequency genetic alterations in mediators of signaling by the TGF-β superfamily [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 3382.