Abstract 849: Molecular characterization of primary tumor & the paired liver metastatic biopsies of colorectal cancer reveals a critical role of immunosuppression, EMT & angiogenesis in cancer metastasis
Authors: Liu Jiangang , Cho Yong Beom , Hong Hye kyung , Wu Song , Ebert Philip J. , Bray Steven M. , Wong Swee Seong , Ting Jason C. , Calley John N. , Whittington Catherine F. , Bhagwat Shripad , Bowden Emma , Aggarwal Amit , Reinhard Christoph , Wild Robert , Nam Do-Hyun , Lee Woo Yong , Peng Sheng-Bin 
Published: July 2017

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. In United States alone, it was estimated that nearly 137,000 people were diagnosed, and more than 50,000 were dead from the disease each year. CRC primary tumors often metastasize to liver which accounts for most of CRC death. The molecular mechanism of tumor metastasis is complicate and remains poorly understood. In this study, we have collected 79 human CRC samples, and 60 of them are paired primary tumor and liver metastatic surgically resected samples. Molecular characterization of these samples was conducted by exome and RNA sequencing, as well as SNP6.0 analysis. Genetic analysis revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and their matched liver metastatic tumors. To further characterize the molecular mechanism of metastatic progression, we have assembled gene correlation networks by utilizing a genome-wide interrogation of co-regulated networks based on RNA sequencing data of these CRC samples. Computational analysis of these correlation networks has identified gene signatures of immune-suppression, epithelial-mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets verified that these specific gene networks of tumor microenvironment were progressively up-regulated throughout the carcinogenesis, and represented distinct biological processes. These gene networks were capable of discriminating the previously categorized CRC molecular subclasses. In addition, we also showed an association of type I interferon network with good clinical outcome of CRC, and gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely associated with the poor patient outcome. We further demonstrated that the networks of EMT and angiogenesis were related to innate anti-PD-1 resistance, and the networks of immunosuppression and T cell exhaustion were associated with resistance to radiation and checkpoint blockade. Overall, we conclude that a genome-wide interrogation of co-regulated networks utilized in this study represents a valuable strategy to identify molecular mechanisms of cancer metastasis, and gene networks of immune-suppression, EMT and angiogenesis are among the key events associated with CRC metastasis.

Citation Format: Jiangang Liu, Yong Beom Cho, Hye kyung Hong, Song Wu, Philip J. Ebert, Steven M. Bray, Swee Seong Wong, Jason C. Ting, John N. Calley, Catherine F. Whittington, Shripad Bhagwat, Emma Bowden, Amit Aggarwal, Christoph Reinhard, Robert Wild, Do-Hyun Nam, Woo Yong Lee, Sheng-Bin Peng. Molecular characterization of primary tumor & the paired liver metastatic biopsies of colorectal cancer reveals a critical role of immunosuppression, EMT & angiogenesis in cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 849. doi:10.1158/1538-7445.AM2017-849