A Novel Prognostic Biomarker Panel for Early-Stage Colon Carcinoma

Azcue, Pablo; Setas, David Guerrero; Encı́o, Ignacio; Ibáñez, Berta; Mercado, María; Vera, Ruth; Gómez-Dorronsoro, M.L.

doi:10.3390/cancers13235909

Cited by 6 publications

(3 citation statements)

References 87 publications

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“…Three-μm sections of tissue microarrays (TMAs) blocks harboring four tumor-carrying cores selected by the pathologist were placed on slides and then deparaffinized, hydrated and treated to block endogenous peroxidase activity using Vision Biosystems Bond-Max (Leica, Wetzlar, Germany) and Bench-Mark XT Ventana (Roche, Basel, Switzerland) automatic immunostaining apparatus, as previously published [ 64 ]. These slides were incubated with the appropriate primary antibodies against mismatch repair proteins-MMR (MLH1, MSH2, MSH6) and against proteins of the subrogate panel (CDX2, FRMD6, HTR2B and ZEB1) under the conditions summarized in Additional file 5 : Table 1.…”

Section: Methodsmentioning

confidence: 99%

ZEB1 hypermethylation is associated with better prognosis in patients with colon cancer

Fernandez-De-Los-Reyes,

Gomez-Dorronsoro,

Monreal-Santesteban

et al. 2023

Clin Epigenet

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Background Colon cancer (CC) is a heterogeneous disease that is categorized into four Consensus Molecular Subtypes (CMS) according to gene expression. Patients with loco-regional CC (stages II/III) lack prognostic factors, making it essential to analyze new molecular markers that can delineate more aggressive tumors. Aberrant methylation of genes that are essential in crucial mechanisms such as epithelial mesenchymal transition (EMT) contributes to tumor progression in CC. We evaluate the presence of hyper- and hypomethylation in subrogate IHC markers used for CMS classification (CDX2, FRMD6, HTR2B, ZEB1) of 144 stage II/III patients and CC cell lines by pyrosequencing. ZEB1 expression was also studied in control and shRNA-silenced CC cell lines and in paired normal tissue/tumors by quantitative PCR. The pattern of ZEB1 staining was also analyzed in methylated/unmethylated tumors by immunohistochemistry. Results We describe for the first time the hypermethylation of ZEB1 gene and the hypomethylation of the FRMD6 gene in 32.6% and 50.9% of tumors, respectively. Additionally, we confirm the ZEB1 re-expression by epigenetic drugs in methylated cell lines. ZEB1 hypermethylation was more frequent in CMS1 patients and, more importantly, was a good prognostic factor related to disease-free survival (p = 0.015) and overall survival (p = 0.006) in our patient series, independently of other significant clinical parameters such as patient age, stage, lymph node involvement, and blood vessel and perineural invasion. Conclusions Aberrant methylation is present in the subrogate genes used for CMS classification. Our results are the first evidence that ZEB1 is hypermethylated in CC and that this alteration is an independent factor of good prognosis.

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Section: Methodsmentioning

confidence: 99%

ZEB1 hypermethylation is associated with better prognosis in patients with colon cancer

Fernandez-De-Los-Reyes,

Gomez-Dorronsoro,

Monreal-Santesteban

et al. 2023

Clin Epigenet

Self Cite

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“…Numerous studies analyzed the gene transcriptional levels of colon cancer patients and found key genes such as GLUT1, MUC2, Cyclooxygenase-2, etc. that are related to the prognosis of colon cancer [3,4]. Recent studies on colon cancer-related gene regulatory pathways found that MAPK signaling pathway, JAK/STAT, AKT/NF-κB and other signaling pathways can modulate the occurrence of colon cancer [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

The expression of SERPINE1 in colon cancer and its regulatory network and prognostic value

Wang¹,

Wang²,

Gao³

et al. 2023

BMC Gastroenterol

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Background Serpin Peptidase Inhibitor 1 (SERPINE1) promotes cancer progression by making it easier for cancer cells to spread to surrounding normal tissue. We expect to understand the prognostic value and regulatory network of SERPINE1 in colon cancer using bioinformatics methods. Methods The expression of target gene SERPINE1 in varying cancers was analyzed by the Tumor Immune Estimation Resource (TIMER) database. SERPINE1 expression in Colon Adenocarcinoma and normal tissue samples was assessed by starBase and UALCAN databases. SERPINE1 expression in clinical tissues was assayed using quantitative reverse transcription Polymerase Chain Reaction (qRT-PCR). SERPINE1 expression was detected in colon cancer patients with various clinical features (age, gender, nodal metastasis status, race, stages, and subtype) using analysis of variance. Survival curve was used to analyze the effect of high and low expression of SERPINE1 on the survival time of patients with different clinical phenotypes. Gene Set Enrichment Analysis (GSEA) was conducted on the results of LinkFinder calculation using LinkInterpreter module, which was combined with Pearson correlation analysis to obtain the kinase targets and miRNA targets, transcription factor targets, and corresponding signaling pathways associated with SERPINE1. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed on GSEA result. Finally, Gene Multiple Association Network Integration Algorithm (GeneMANIA) was utilized to establish a network of genes related to the kinases MAPK1, miR-18a, and SRF_Q, and biological functions were analyzed. Results Based on TIMER, starBase, and UALCAN databases, SERPINE1 was found to be remarkably highly expressed in colon cancer patients, which was further verified by clinical tissue. It was also associated with different clinical features (nodal metastasis status, stages, subtypes). Additionally, survival analysis showed that patients with low expression of SERPINE1 had a longer survival time, suggesting that SERPINE1 was a prognostic risk factor for colon cancer. Pearson correlation analysis revealed that the expression of Integrin Alpha 5 (ITGA5), Matrix Metallopeptidase 19 (MMP19), and ADAM Metallopeptidase with Thrombospondin Type 1 Motif, 4 (ADAMTS4) had the highest correlation with that of SERPINE1. The GSEA results indicated that these genes were mainly enriched in the pathways of RNA expression and kinases. Finally, GeneMANIA analysis was introduced to construct the molecular network of SERPINE1. Conclusion Overall, our bioinformatics analyses comprehensively described the networks involved SERPINE1 in colon cancer and the potentially associated molecular mechanisms.

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“…Numerous groups have since reproduced the prognostic claims [11][12][13][14][15][16][17][18][19][20][21][22][23][24] . Thirty-two independent studies, involving >13,000 unique subjects, most that used IHC and one that used IHC in combination with quantitative mass spectrometry 25 , have determined that CDX2-neg CRCs are associated with lower overall survival (OS) and DFS independent of ethnicity, DNA mismatch repair (MMR) status or stage 7,20,24,26 [Figure 1- Step 1].…”

Section: Introductionmentioning

confidence: 99%

Machine-Learning Identifies a Strategy for Differentiation Therapy in Solid Tumors

Sinha,

Alcantara,

Perry

et al. 2023

Preprint

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Background: Lack of expression of the transcription factor CDX2 identifies a subset of poorly differentiated colorectal cancers (CRCs) that are associated with lower overall (OS) and disease-free (DFS) survival, independent of ethnicity, MSI status, or stage. Reinstatement of CDX2 is predicted to lower the risk of death and recurrence by 50% but such a therapeutic strategy is yet to emerge. Methods: A network-based computational model, validated using healthy colon and CRC tissues in diverse gene expression datasets (~5,000 human and >300 mouse samples), was used to identify therapeutic targets that can augment CDX2 expression. The top candidate with available clinical-grade drug (PRKAB1) was tested on 3 models: CRC lines in vitro, xenografts in mice, and in a prospective cohort of healthy (n = 3) and CRC (n = 23) patient-derived organoids (PDOs). Results: In all 3 models, PRKAB1-agonism predictably shifted the network, induced CDX2 and crypt differentiation signatures and showed selective cytotoxicity towards CDX2-negative CRCs. Xenotransplantation studies in mice reduced tumour volume by 68% and abolished mortality (Hazard ratio; H.R = 0.09). Effective pairing of therapeutic efficacy (IC50 for PRKAB1-agonism) and biomarker (CDX2-low state) was validated in an independent cohort of PDOs. A multivariate analysis revealed CDX2-low state as the key determinant of therapeutic efficacy. A 50-gene signature of therapeutic response tested on 9 cohorts (n = 1701 patients) showed that CDX2-reinstatement therapy will reduce the risk of mortality/recurrence by ~50%. Conclusions: CDX2-reinstatement therapy selectively triggers cell differentiation and death in CDX2-low CRCs. Realization of the benefit of such therapy-biomarker pairing requires confirmatory studies in randomized clinical trials.

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A Novel Prognostic Biomarker Panel for Early-Stage Colon Carcinoma

Cited by 6 publications

References 87 publications

ZEB1 hypermethylation is associated with better prognosis in patients with colon cancer

ZEB1 hypermethylation is associated with better prognosis in patients with colon cancer

The expression of SERPINE1 in colon cancer and its regulatory network and prognostic value

Machine-Learning Identifies a Strategy for Differentiation Therapy in Solid Tumors

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