Abstract
BackgroundNeurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC).MethodsAn analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP).ResultsThe profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma.ConclusionsThis study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer death over the past years [1, 2]
Neurotrophic tropomyosin receptor kinases (NTRKs) gene was commonly suppressed by DNA methylation in CRCUsing the methylation profile we previously generated through 450K microarray, we found NTRKs gene, including Neurotropic tropomyosin receptor kinase 1 (NTRK1), Neurotropic tropomyosin receptor kinase 2 (NTRK2) and Neurotropic tropomyosin receptor kinase 3 (NTRK3), had more frequently methylated promoters in colorectal cancer (CRC) samples when compared with matched normal mucosae (NTRK1, cancer = 0.444, normal = 0.397, P = 0.012; NTRK2, cancer = 0.251, normal = 0.167, P < 0.001; NTRK3, cancer = 0.395, normal = 0.144, P < 0.001; Fig. 2; Additional file 1: Table S2)
In support of methylation analysis results, we found the mRNA expression of NTRK2 and NTRK3 in CRC samples was commonly lower than that in normal mucosae using the expression profiles in four CRC cohorts (n = 1410)
Summary
Colorectal cancer (CRC) is the second leading cause of cancer death over the past years [1, 2]. Some clinicopathological risk factors, such as TNM stage, tumor size, and tumor differentiation, have been used to stratify the risk of CRC death They fail to accurately distinguish patients with different outcomes [3], and several molecular biomarkers are being investigated and applied in current. The aberrant methylation in gene promoters is prevalent across multiple cancers, which can lead to the inactivation of tumor suppressor genes [8]. Some of these aberrant methylations have been discovered and used to serve as prognostic biomarkers for CRC [9, 10]. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC)
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