Abstract 1971: ITGBL1 is a novel epithelial mesenchymal transition-associated prognostic biomarker in colorectal cancer
Authors: Matsuyama Takatoshi , Ishikawa Toshiaki , Takahashi Naoki , Yamada Yasuhide , Yasuno Masamichi , Kawano Tatsuyuki , Uetake Hiroyuki , Goel Ajay 
Published: July 2017

Purpose: Colorectal cancer (CRC) ranks as the third leading cancer worldwide, and its incidence continues to rise gradually, highlighting the need to stratify the risk of recurrence after curative surgery. Recently, several genes have been identified which appear to associate with metastasis, as they mediate epithelial-to-mesenchymal transition (EMT) in cancer. This study aimed to identify novel EMT and cancer recurrence-associated biomarkers through systematic and comprehensive discovery and validated strategy in multiple, independent CRC cohorts.

Experimental Design: Two independent gene expression microarray datasets (n =173 and n =307 respectively) were used to identify novel metastasis-recurrence biomarkers for CRC. Following carefully selection and prioritization of biomarkers, we selected a candidate gene and validated its performance as a recurrence marker in a large testing cohort (n=566), and two independent clinical validation cohorts (n=201, n=475, respectively). To confirm the protein expression of ITGBL1 in cancer, immunohistochemistry (IHC) was performed in paired 33 primary CRCs and adjacent normal mucosa, as well as a subset of liver and lung metastases tissues. In addition, we used Gene Set Enrichment Analysis (GSEA) to determine the functional role of ITGBL1 in CRC.

Results: During the discovery step, gene expression profiles from differentially expressed genes between recurrence positive and negative primary CRCs, as well as evaluation of the metastatic sites compared with primary CRC, identified ITGBL1 as a most promising candidate biomarker. High expression of ITGBL1 associated with poor overall survival (OS) in stage I-IV patients and worse disease-free survival (DFS) in stage I-III patients. Subgroup validation of these results in two large and independent patient cohorts confirmed these findings and demonstrated that high ITGBL1 expression correlated with shorter DFS in stage II and III CRC patients. In addition, high ITGBL1 expression emerged as an independent prognostic factor for DFS in stage II and III patients. IHC analysis revealed that both early stage CRCs and adjacent normal colonic mucosa displayed low ITGBL1 expression, while ITGBL1 expression gradually increased from tumor surface to the invasive front in late stage cancer, indicating that ITGBL1 may facilitate EMT process and promote a more aggressive phenotype in CRC.

Conclusions: High expression of ITGBL1 in primary tumors was associated with tumor recurrence in CRC patients after curative surgery. Collectively, we have identified ITGBL1 as a novel EMT-associated biomarker which could be used for risk stratification for metastatic potential in CRC.

Citation Format: Takatoshi Matsuyama, Toshiaki Ishikawa, Naoki Takahashi, Yasuhide Yamada, Masamichi Yasuno, Tatsuyuki Kawano, Hiroyuki Uetake, Ajay Goel. ITGBL1 is a novel epithelial mesenchymal transition-associated prognostic biomarker in colorectal cancer [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 1971. doi:10.1158/1538-7445.AM2017-1971