Abstract 3135: Genomewide expression profiling identifies a novel miRNA-based signature for the detection of peritoneal metastasis in gastric cancer

Abstract

Abstract Purpose: Even though peritoneal metastasis (PM) in patients with gastric cancer (GC) has long been recognized to associate with poor survival, currently there is a lack of availability of biomarkers for its robust diagnosis. Availability of such biomarkers will facilitate more accurate identification of PM in GC patients, and could be clinically transformative as it will permit a timely intervention leading to reduced mortality associated with this malignancy. Recent advances in next generation sequencing technologies for an in-depth genomic and epigenomic profiling of various malignancies has paved the path for identification of previously unrecognized biomarkers. One such molecular substrates includes microRNAs (miRNAs), which are 18-25 nucleotides long, single-stranded noncoding RNAs, and act as post-transcriptional gene repressors. Although expression of specific miRNAs is frequently dysregulated in various human cancers including GC, their clinical significance as potential biomarkers for detecting PM has not been evaluated in large, adequately powered, independent patient cohorts. Accordingly, in this study, we undertook a comprehensive effort to identify and establish a novel miRNA-based signature for diagnosing presence of PM in GC patients. Experimental design: We performed a genomewide, systematic biomarker discovery by analyzing miRNA expression profiles in primary tumors from GC patients with and without PM, followed by independent testing and validation in multiple patient cohorts of 354 patients, and establishment of a miRNA-signature for the diagnosis of PM in patients with advanced GC. Results: Five miRNAs (miR-30a-5p, -134-5p, -337-3p, -659-3p, and -3917) were identified during the initial discovery phase; three of which (miR-30a-5p, -659-3p, and -3917) were significantly overexpressed in the primary tumors from PM-positive patients in the testing cohort (p=0.002, 0.04 and 0.007 respectively), and robustly distinguished patients with vs. without PM (AUC=0.82). Furthermore, high expression of these miRNAs was also associated with poor prognosis (HR=2.18, p=0.04). The efficacy of the combination miRNA-signature was successfully validated in an independent patient cohort (AUC=0.74). Finally, this miRNA signature in combination with the macroscopic Borrmann’s type score offered a significantly superior diagnostic accuracy in all three cohorts (AUC=0.87, 0.76, 0.79, respectively), and led to the establishment of a risk-prediction nomogram for the diagnosis of PM in GC patients. Conclusions: Using a genomewide transcriptomic profiling biomarker discovery and validation approach, we have established a novel miRNA-signature that robustly identifies presence of peritoneal metastasis in gastric cancer patients, which might lead to improved survival outcomes in patients suffering from this malignancy. Citation Format: Tadanobu Shimura, Shusuke Toden, Raju Kandimalla, Yuji Toiyama, Yoshinaga Okugawa, Mitsuro Kanda, Hideo Baba, Yasuhiro Kodera, Masato Kusunoki, Hiroki Hori, Ajay Goel. Genomewide expression profiling identifies a novel miRNA-based signature for the detection of peritoneal metastasis in gastric cancer [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 3135.