Colon cancer molecular subtypes identified by expression profiling and associatedto stroma, mucinous type and different clinical behavior

Abstract

Background Colon cancer patients with the same stage show diverse clinical behavior dueto tumor heterogeneity. We aimed to discover distinct classes of tumorsbased on microarray expression patterns, to analyze whether the molecularclassification correlated with the histopathological stages or otherclinical parameters and to study differences in the survival. Methods Hierarchical clustering was performed for class discovery in 88 colon tumors(stages I to IV). Pathways analysis and correlations between clinicalparameters and our classification were analyzed. Tumor subtypes werevalidated using an external set of 78 patients. A 167 gene signatureassociated to the main subtype was generated using the 3-Nearest-Neighbormethod. Coincidences with other prognostic predictors were assesed. Results Hierarchical clustering identified four robust tumor subtypes withbiologically and clinically distinct behavior. Stromal components(p < 0.001), nuclear β-catenin (p = 0.021),mucinous histology (p = 0.001), microsatellite-instability(p = 0.039) and BRAF mutations (p < 0.001) wereassociated to this classification but it was independent of Dukes stages(p = 0.646). Molecular subtypes were established from stage I.High-stroma-subtype showed increased levels of genes and altered pathwaysdistinctive of tumour-associated-stroma and components of the extracellularmatrix in contrast to Low-stroma-subtype. Mucinous-subtype was reflected bythe increased expression of trefoil factors and mucins as well as by ahigher proportion of MSI and BRAF mutations. Tumor subtypes werevalidated using an external set of 78 patients. A 167 gene signatureassociated to the Low-stroma-subtype distinguished low risk patients fromhigh risk patients in the external cohort (Dukes B andC:HR = 8.56(2.53-29.01); Dukes B,C andD:HR = 1.87(1.07-3.25)). Eight different reported survival genesignatures segregated our tumors into two groups the Low-stroma-subtype andthe other tumor subtypes. Conclusions We have identified novel molecular subtypes in colon cancer with distinctbiological and clinical behavior that are established from the initiation ofthe tumor. Tumor microenvironment is important for the classification andfor the malignant power of the tumor. Differential gene sets and biologicalpathways characterize each tumor subtype reflecting underlying mechanisms ofcarcinogenesis that may be used for the selection of targeted therapeuticprocedures. This classification may contribute to an improvement in themanagement of the patients with CRC and to a more comprehensiveprognosis.

Gene expression profiling-derived immunohistochemistry signature with high prognostic value in colorectal carcinoma

“…The top overlapping genes in the 25 signatures were POSTN (six times), followed by CYP1B1 and SPP1 (five times), 23 genes (three times), and 155 genes (twice). We excluded five signatures without information of gene expression direction 7 9 11 12 26. The remaining 20 gene signatures were subjected for nearest template prediction analyses in each of four combined microarray datasets from Affymetrix platforms (see online supplementary tables S4 and S5).…”

Development of a deregulating MicroRNA panel for the detection of early relapse in postoperative colorectal cancer patients

“…a-f Disease-free survival was significantly shorter in CRC patients in the high miR-7 (a, P = 0.033), miR-141 (c, P < 0.0001), and miR-494 (e, P = 0.03) expression subgroups. Disease-free survival was significantly longer in CRC patients in the high miR-93 (b, P < 0.0001), miR-195 (c, P = 0.002), and let-7b (e, P = 0.015) expression subgroups Yang et al J Transl Med (2016) 14:108 There are significant differences in UICC stage, location, type of tumor, vascular invasion, perineural invasion and lymph node metastasis between the non-early relapsed and early relapsed group, these may due to the gene expression profile or miR expression profile difference or tumors with different clinicopathologic characteristics [8,9,[52][53][54][55][56]. To date, carcinoembryonic antigen (CEA) is the recommended tumor marker for the postoperative surveillance of CRC recurrence in clinical practice.…”

A 50-gene signature is a novel scoring system for tumor-infiltrating immune cells with strong correlation with clinical outcome of stage I/II non-small cell lung cancer

“…Gene expression profiles of 84 NSCLC were determined using two-color Agilent Microarrays (G4112F) as explained in Perez-Villamil et al [18]. A pool of RNA obtained from 42 normal lung parenchyma samples was used as reference.…”