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

ABSTRACT: BACKGROUND: Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical 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 clinical parameters and our classification were analyzed. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the main subtype was generated using the 3-Nearest-Neighbor method. Coincidences with other prognostic predictors were assesed. RESULTS: Hierarchical clustering identified four robust tumor subtypes with biologically and clinically distinct behavior. Stromal components (p?

SUBMITTER: Perez-Villamil B

PROVIDER: S-EPMC3571914 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Perez-Villamil Beatriz B Romera-Lopez Alejandro A Hernandez-Prieto Susana S Lopez-Campos Guillermo G Calles Antonio A Lopez-Asenjo Jose-Antonio JA Sanz-Ortega Julian J Fernandez-Perez Cristina C Sastre Javier J Alfonso Rosario R Caldes Trinidad T Martin-Sanchez Fernando F Diaz-Rubio Eduardo E

BMC cancer 20120619

<h4>Background</h4>Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters and to study differences in the survival.<h4>Methods</h4>Hierarchical clustering was performed for class discovery in 88 colon tumors (stages I to IV). Pathways analysis ...[more]

PMID: 22712570

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Project description:OBJECTIVE:Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN:We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS:We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-? as potential therapeutic immune targets. CONCLUSIONS:We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.

Dataset Information

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

Publications

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

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