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Plasma Protein Profiling Reveal Osteoprotegerin as a Marker of Prognostic Impact for Colorectal Cancer.

ABSTRACT: BACKGROUND:Due to difficulties in predicting recurrences in colorectal cancer stages II and III, reliable prognostic biomarkers could be a breakthrough for individualized treatment and follow-up. OBJECTIVE:To find potential prognostic protein biomarkers in colorectal cancer, using the proximity extension assays. METHODS:A panel of 92 oncology-related proteins was analyzed with proximity extension assays, in plasma from a cohort of 261 colorectal cancer patients with stage II-IV. The survival analyses were corrected for disease stage and age, and the recurrence analyses were corrected for disease stage. The significance threshold was adjusted for multiple comparisons. RESULTS:The plasma proteins expression levels had a greater prognostic relevance in disease stage III colorectal cancer than in disease stage II, and for overall survival than for time to recurrence. Osteoprotegerin was the only biomarker candidate in the protein panel that had a statistical significant association with overall survival (P = .00029). None of the proteins were statistically significantly associated with time to recurrence. CONCLUSIONS:Of the 92 analyzed plasma proteins, osteoprotegerin showed the strongest prognostic impact in patients with colorectal cancer, and therefore osteoprotegerin is a potential predictive marker, and it also could be a target for treatments.

SUBMITTER: Birgisson H

PROVIDER: S-EPMC6037900 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Plasma Protein Profiling Reveal Osteoprotegerin as a Marker of Prognostic Impact for Colorectal Cancer.

Birgisson Helgi H Tsimogiannis Kostas K Freyhult Eva E Kamali-Moghaddam Masood M

Translational oncology 20180704 4

<h4>Background</h4>Due to difficulties in predicting recurrences in colorectal cancer stages II and III, reliable prognostic biomarkers could be a breakthrough for individualized treatment and follow-up.<h4>Objective</h4>To find potential prognostic protein biomarkers in colorectal cancer, using the proximity extension assays.<h4>Methods</h4>A panel of 92 oncology-related proteins was analyzed with proximity extension assays, in plasma from a cohort of 261 colorectal cancer patients with stage I ...[more]

PMID: 29982101

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Project description:IntroductionColorectal cancer (CRC) testing programs reduce mortality; however, approximately 40% of the recommended population who should undergo CRC testing does not. Early colon cancer detection in patient populations ineligible for testing, such as the elderly or those with significant comorbidities, could have clinical benefit. Despite many attempts to identify individual protein markers of this disease, little progress has been made. Targeted mass spectrometry, using multiple reaction monitoring (MRM) technology, enables the simultaneous assessment of groups of candidates for improved detection performance.Materials and methodsA multiplex assay was developed for 187 candidate marker proteins, using 337 peptides monitored through 674 simultaneously measured MRM transitions in a 30-minute liquid chromatography-mass spectrometry analysis of immunodepleted blood plasma. To evaluate the combined candidate marker performance, the present study used 274 individual patient blood plasma samples, 137 with biopsy-confirmed colorectal cancer and 137 age- and gender-matched controls. Using 2 well-matched platforms running 5 days each week, all 274 samples were analyzed in 52 days.ResultsUsing one half of the data as a discovery set (69 disease cases and 69 control cases), the elastic net feature selection and random forest classifier assembly were used in cross-validation to identify a 15-transition classifier. The mean training receiver operating characteristic area under the curve was 0.82. After final classifier assembly using the entire discovery set, the 136-sample (68 disease cases and 68 control cases) validation set was evaluated. The validation area under the curve was 0.91. At the point of maximum accuracy (84%), the sensitivity was 87% and the specificity was 81%.ConclusionThese results have demonstrated the ability of simultaneous assessment of candidate marker proteins using high-multiplex, targeted-mass spectrometry to identify a subset group of CRC markers with significant and meaningful performance.

Project description: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.

Project description:Purpose: This study aimed to identify a novel biomarker or a target of treatment for colorectal cancer (CRC). Experimental Design: The expression profiles of cancer cells in 104 patients with CRC were examined using laser microdissection and oligonucleotide microarray analysis. Overexpression in CRC cells especially in patients with distant metastasis was a prerequisite to select candidate genes. The mRNA expression of candidate gene was investigated by quantitative reversetranscription polymerase chain reaction (RT-PCR) in 77 patients as a validation study. We analyzed the protein expression and localization of the candidate gene by immunohistochemical study, and investigated the relationship between the expression and the clinicopathological feature in 274 CRC patients. Results: We identified 6 genes as candidates related to distant metastasis in CRC patients by microarray analysis. Among these genes, Osteoprotegerin (OPG) is known to have an association with aggressiveness in several cancers through inhibiting apoptosis by neutralizing the function of tumor necrosis factor related apoptosis inducing ligand (TRAIL). The mRNA expression of OPG in cancer tissues was significantly higher in patients with distant metastasis than those without metastasis. The overexpression of OPG protein was significantly associated with worse overall survival and relapse free survival (RFS). Moreover, the overexpression of OPG protein was an independent risk factor for recurrence of CRC. Conclusion: The overexpression of OPG would be a predictive biomarker of recurrence and a target of the treatment for CRC. Total of 148 microarray datasets obtained from LCM and homogenized tissues of colorectal cancer patients were normalized using robust multi-array average (RMA) method under R 2.6.2 statistical software with affy package from BioConductor. Normalization was separately performed for LCM dataset and homogenized tissue dataset. The normalized gene expression levels were presented as log2-transformed values by RMA.

Project description:BackgroundAlthough circular RNAs (circRNAs) have recently garnered interest as disease markers, they have been relatively poorly studied as a biomarker in colorectal cancer (CRC). In this study, we aimed to screen the exosome-derived circRNAs in CRC and explore their potential as diagnostic and prognostic biomarkers of CRC METHODS: Exosomes were extracted from the plasma using a kit and validated by immunoblotting, transmission electron microscopy, and particle size analysis. The microarray datasets were employed to identify differentially-expressed circRNAs from plasma exosomes. Real-time quantitative reverse transcription PCR (RT-qPCR) verified the results of the microarray analysis, and Receiver operating characteristic (ROC) curve revealed the diagnostic ability of a single circRNA. The Starbase combined with microT, miRmap, and RNA22 were used to establish a circRNA-miRNA-mRNA network. Gene ontology, Kyoto Encyclopedia of Genes, Genomes pathway enrichment analysis, and Gene Set Enrichment Analysis were applied to determine potential functions of the identified mRNAs RESULTS: Comparing the microarray of plasma exosome-derived circRNAs and the microarray downloaded from the GEO database, 15 candidate circRNAs with up-regulated expression were identified. RT-qPCR verified that hsa_circ_0003270 (circGAPVD1) was upregulated in CRC plasma exosomes. ROC analysis showed that circGAPVD1 in plasma exosomes has potential diagnostic value for CRC. The sensitivity and specificity of circGAPVD1 in the diagnosis of CRC were found to be 75.64 and 71.79%, respectively (area under ROC = 0.7662). Furthermore, the lymph node metastasis and TNM staging of patients were positively correlated with high expression of circGAPVD1. Combined with the ENCORI database and GEO datasets, we identified the circGAPVD1-related ceRNA network. The enrichment analysis revealed that key nodes in the ceRNA network participate in many important signaling pathways such as protein post-translational modifications CONCLUSION: Our results revealed the diagnostic efficiency of circGAPVD1 in plasma exosomes. The highly expressed circGAPVD1 is expected to be a novel diagnostic marker for CRC.

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Plasma Protein Profiling Reveal Osteoprotegerin as a Marker of Prognostic Impact for Colorectal Cancer.

Publications

Plasma Protein Profiling Reveal Osteoprotegerin as a Marker of Prognostic Impact for Colorectal Cancer.

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