Abstract 2226: TGF-β and CEACAMs regulated biomarkers detect early colorectal cancer
Authors: Sobia Zaidi, Anil Korkut, Wilma Jogunoori, Jian Chen, Shoujun Gu, Shuyun Rao, Kazufumi Ohshiro, Rehan Akbani, Chuxia Deng, Bibhuti Mishra, Lopa Mishra
Journal: Cancer Research (2018)

Abstract Introduction: Development of colorectal cancer (CRC) is associated with alterations in key driving pathways, which include Wnt (APC-βcatenin), TGF-β members, p53 and pathways that regulate Ras activity. Members of the TGF-β superfamily regulate colon inflammation, have both tumor-suppressing and tumor-promoting activities, while colon cancer formation has been observed in TGF-β deficient mouse models. Through earlier studies, using mouse models followed by functional studies in human cell lines and tissues, we identified candidate set of TGF-β regulated biomarkers for early detection of CRC, that were altered in tissues from patients with adenomas, and could represent signs of early cancer stem cell development (J Clin Invest 2016;126(2); PLoS One 2016;11(4)). These markers are CEACAMs 1, 5 and 6; TGFBR2, SMAD4, Smad adaptor, SPTBN1. Here, we took an integrated approach to extend and validate these potential markers for early detection of CRC. Methods and Results: 1) Analyzing the TCGA cohort of 9,125 samples and 33 cancer types, including CRC, revealed alterations in TGF-β members in ~40% of samples. 2) cBioportal cancer genomics data reveal reduced overall survival in CRC patients with decreased TGFBR1 and TGFBR2, together with increased CEA (CEACAM5). 3) TCGA analyses also reveal significant tendency of co-occurrence of genomic alterations in TGFBR1 and CEA. 4) mRNA stemness index score in 33 cancers types in TCGA, reveals increased transcriptome levels of a cancer stem cell signature in specific cancers, that concomitantly have decreased levels of TGF-β pathway members, supporting the mouse models revealing that TGF-β suppresses cancer stem cells. 5) Cluster analysis for miRNAs in the 33 cancers suggest a role for these in suppression of TGF-β pathway, depending on the cancer type. miRNA 92a-3p that targets 3 core genes, BMPR2, TGFBR2, and SMAD7, is overexpressed in many cancers. Colon cancer with high frequencies of hotspot mutations in BMPR2 and TGFBR2 did not have high expression of 92a-3p, perhaps indicating that there is little selective pressure for a second mechanism of inactivation. 6) We further identified hotspot mutations in the B3 domain of the CEA that interacts with TGFBR1, supporting a mechanism for previously observed CEA inactivation of TGF-β tumor suppressor function. Conclusions: CEACAMs with TGF-β signaling members as a group could represent strong prognostic indicators of high-risk adenoma-carcinoma progression and invasive disease. Citation Format: Sobia Zaidi, Anil Korkut, Wilma Jogunoori, Jian Chen, Shoujun Gu, Shuyun Rao, Kazufumi Ohshiro, Rehan Akbani, Chuxia Deng, Bibhuti Mishra, Lopa Mishra. TGF-β and CEACAMs regulated biomarkers detect early colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2226.