T Ozawa1, T Matsuyama1, Y Toiyama2, N Takahashi3, T Ishikawa4, H Uetake4, Y Yamada3, M Kusunoki2, G Calin5, A Goel1. 1. Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, USA. 2. Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie Japan. 3. Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo Japan. 4. Department of Specialized Surgery, Tokyo Medical and Dental University, Tokyo, Japan. 5. Division of Cancer Medicine, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA.
Abstract
BACKGROUND: 8q24.21 is a frequently amplified genomic region in colorectal cancer (CRC). This region is often referred to as a 'gene desert' due to lack of any important protein-coding genes, highlighting the potential role of noncoding RNAs, including long noncoding RNAs (lncRNAs) located around the proto-oncogene MYC. In this study, we have firstly evaluated the clinical significance of altered expression of lncRNAs mapped to this genomic locus in CRC. PATIENTS AND METHODS: A total of 300 tissues, including 280 CRC and 20 adjacent normal mucosa specimens were evaluated for the expression of 12 lncRNAs using qRT-PCR assays. We analyzed the associations between lncRNA expression and various clinicopathological features, as well as with recurrence free survival (RFS) and overall survival (OS) in two independent cohorts. RESULTS: The expression of CCAT1, CCAT1-L, CCAT2, PVT1, and CASC19 were elevated in cancer tissues (P = 0.039, <0.001, 0.018, <0.001, 0.002, respectively). Among these, high expression of CCAT1 and CCAT2 was significantly associated with poor RFS (P = 0.049 and 0.022, respectively) and OS (P = 0.028 and 0.015, respectively). These results were validated in an independent patient cohort, in which combined expression of CCAT1 and CCAT2 expression was significantly associated with a poor RFS (HR:2.60, 95% confidence interval [CI]: 1.04-6.06, P = 0.042) and a poor OS (HR:8.38, 95%CI: 2.68-37.0, P < 0.001). We established a RFS prediction model which revealed that combined expression of CCAT1, CCAT2, and carcinoembryonic antigen was a significant determinant for efficiently predicting RFS in stage II (P = 0.034) and stage III (P = 0.001) CRC patients. CONCLUSIONS: Several lncRNAs located in 8q24.21 locus are highly over-expressed in CRC. High expression of CCAT1 and CCAT2 significantly associates with poor RFS and OS. The expression of these two lncRNAs independently, or in combination, serves as important prognostic biomarkers in CRC.
BACKGROUND: 8q24.21 is a frequently amplified genomic region in colorectal cancer (CRC). This region is often referred to as a 'gene desert' due to lack of any important protein-coding genes, highlighting the potential role of noncoding RNAs, including long noncoding RNAs (lncRNAs) located around the proto-oncogene MYC. In this study, we have firstly evaluated the clinical significance of altered expression of lncRNAs mapped to this genomic locus in CRC. PATIENTS AND METHODS: A total of 300 tissues, including 280 CRC and 20 adjacent normal mucosa specimens were evaluated for the expression of 12 lncRNAs using qRT-PCR assays. We analyzed the associations between lncRNA expression and various clinicopathological features, as well as with recurrence free survival (RFS) and overall survival (OS) in two independent cohorts. RESULTS: The expression of CCAT1, CCAT1-L, CCAT2, PVT1, and CASC19 were elevated in cancer tissues (P = 0.039, <0.001, 0.018, <0.001, 0.002, respectively). Among these, high expression of CCAT1 and CCAT2 was significantly associated with poor RFS (P = 0.049 and 0.022, respectively) and OS (P = 0.028 and 0.015, respectively). These results were validated in an independent patient cohort, in which combined expression of CCAT1 and CCAT2 expression was significantly associated with a poor RFS (HR:2.60, 95% confidence interval [CI]: 1.04-6.06, P = 0.042) and a poor OS (HR:8.38, 95%CI: 2.68-37.0, P < 0.001). We established a RFS prediction model which revealed that combined expression of CCAT1, CCAT2, and carcinoembryonic antigen was a significant determinant for efficiently predicting RFS in stage II (P = 0.034) and stage III (P = 0.001) CRC patients. CONCLUSIONS: Several lncRNAs located in 8q24.21 locus are highly over-expressed in CRC. High expression of CCAT1 and CCAT2 significantly associates with poor RFS and OS. The expression of these two lncRNAs independently, or in combination, serves as important prognostic biomarkers in CRC.
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