Survival marker genes of colorectal cancer derived from consistent transcriptomic profiling

Abstract

BackgroundIdentification of biomarkers associated with the prognosis of different cancer subtypes is critical to achieve better therapeutic assistance. In colorectal cancer (CRC) the discovery of stable and consistent survival markers remains a challenge due to the high heterogeneity of this class of tumors. In this work, we identified a new set of gene markers for CRC associated to prognosis and risk using a large unified cohort of patients with transcriptomic profiles and survival information.ResultsWe built an integrated dataset with 1273 human colorectal samples, which provides a homogeneous robust framework to analyse genome-wide expression and survival data. Using this dataset we identified two sets of genes that are candidate prognostic markers for CRC in stages III and IV, showing either up-regulation correlated with poor prognosis or up-regulation correlated with good prognosis. The top 10 up-regulated genes found as survival markers of poor prognosis (i.e. low survival) were: DCBLD2, PTPN14, LAMP5, TM4SF1, NPR3, LEMD1, LCA5, CSGALNACT2, SLC2A3 and GADD45B. The stability and robustness of the gene survival markers was assessed by cross-validation, and the best-ranked genes were also validated with two external independent cohorts: one of microarrays with 482 samples; another of RNA-seq with 269 samples. Up-regulation of the top genes was also proved in a comparison with normal colorectal tissue samples. Finally, the set of top 100 genes that showed overexpression correlated with low survival was used to build a CRC risk predictor applying a multivariate Cox proportional hazards regression analysis. This risk predictor yielded an optimal separation of the individual patients of the cohort according to their survival, with a p-value of 8.25e-14 and Hazard Ratio 2.14 (95% CI: 1.75–2.61).ConclusionsThe results presented in this work provide a solid rationale for the prognostic utility of a new set of genes in CRC, demonstrating their potential to predict colorectal tumor progression and evolution towards poor survival stages. Our study does not provide a fixed gene signature for prognosis and risk prediction, but instead proposes a robust set of genes ranked according to their predictive power that can be selected for additional tests with other CRC clinical cohorts.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5193-9) contains supplementary material, which is available to authorized users.

Regulatory mechanism of lncRNA HCP5 in nasopharyngeal carcinoma cell proliferation and apoptosis via the miR-140-5p/NPR3 axis

“…A recent study has exhibited that patients with NPR3-positive tumors can show remarkably declined progression-free and overall survival [30]. Jorge Martinez-Romero et al have also indicated that NPR3 is upregulated in colorectal cancer samples and considered as a marker of poor outcome [31]. The targeting relationship between miR-140-5p and NPR3 was veri ed in the current study.…”

Identification of Four Pathological Stage-Relevant Genes in Association with Progression and Prognosis in Clear Cell Renal Cell Carcinoma by Integrated Bioinformatics Analysis

“…To explore the occurrence and development of diseases from a novel perspective, bioinformatics analysis is becoming an emerging and effective technique [47,48]. Clear cell renal cell carcinoma is a major histological subtype of renal cell carci-noma, which is one of the deadliest forms of urinary malignancy [1].…”

Multigene panel predicting survival of patients with colon cancer

“…MSLN had been accepted to be a candidate biomarker in colon cancer [37]. Qian Z et al demonstrated that INHBB predicted worse survival rates in patients with colorectal cancer [38] DCBLD2 was also identified as one of survival markers genes in colon cancer through consistent transcriptomic profiling by Martinez-Romero J et al [26]. Gylfe AE et al performed exome sequencing on a total of 25 colorectal cancer and corresponding healthy colon tissues, demonstrating that MAP1B was one of the candidate oncogene in patients with colon cancer [39].…”

“…C-index, also known as concordance" statistic or C-statistic, is a measure of goodness of fit for survival outcomes in a CPH model, and higher C-index means higher predictive ability [21]. Therefore, to further confirm the performance of our multigene panel, we compared the C-indexes, calculated by using the R package "survcomp [22]" , with a total of 10 biomarkers reported by others [23][24][25][26][27][28][29][30][31][32][33]. Student T test was used to compare C-indexes between two groups.…”

“…As mentioned above, we compared the performance of our multigene panel with 10 existing biomarkers (including a 4-gene signature [23], a 15-gene signature [24], two 6-gene signatures [25,28], a 10-gene signature [26], a 5-gene signature [27], AEBP1 [29], FZD7 [30], CDX2 [31], MUC2 [31], PPM1H [32], and LAYN [33]). As shown in figure 6, the C-index of our multigene panel was significantly higher or comparable with the existing biomarkers in the training set, test set, TCGA-COAD, and GSE17536, indicating that our multigene panel had comparable prognostication performance.…”