Unknown,Transcriptomics,Genomics,Proteomics

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Small bowel carcinomas in celiac disease: transcriptomic profiling and comparison with the consensus molecular subtypes of colorectal cancers

ABSTRACT: Purpose: Celiac disease (CD) is a risk factor for developing Small Bowel Carcinoma (SBC) with a 14 folds higher risk than that of the general population. As SBCs associated with CD (CD-SBCs) are extremely rare, very few molecular data are currently available about their pathogenesis and information about CD-SBC transcriptomic profiling is completely lacking. Patients and Methods: We generated RNA-seq data on 13 CD-SBCs selected from the largest and well-characterized series of CD-SBCs published so far that was collected by the Small Bowel Cancer Italian Consortium. In all cases we compared the CD-SBC transcriptional signatures with the four consensus molecular subtypes (CMS) of colorectal carcinoma (CRC) applying the ‘CMS classifier’. CpG Island Methylator Phenotype (CIMP+) was evaluated in all cases using methylation-sensitive multiple ligation-dependent probe amplification. Results: RNA-based signatures of CD-SBCs exhibited strong similarities with CRCs. Twelve of 13 CD-SBCs (92%) fell within the two main subtypes exhibiting high immune and inflammatory signatures, i.e. CMS1 and CMS4. CMS1 CD-SBCs (62% of cases) were commonly MSI/CIMP+ tumors and showed increased expression of genes associated with a diffuse TH1 and cytotoxic T immune infiltrate, up-regulation of apoptosis, cell cycle progression and proteasome pathways. CMS4 CD-SBCs (31% of cases) showed prominent TGF-β activation and were characterized by complement-associated inflammation, matrix remodeling, stromal invasion and angiogenesis Conclusions: RNA-based signatures of CD-SBCs strongly recapitulate CMS classification of CRC, give a promising tool to improve our knowledge of this rare entity and provide clinically useful information using the wealth of data available for CRC.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Antonio Rinaldi

PROVIDER: E-MTAB-7760 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The Colorectal Cancer Subtyping Consortium established four Consensus Molecular Subtypes (CMS) in colorectal cancer: CMS1 (microsatellite-instability [MSI], Immune), CMS2 (Canonical, epithelial), CMS3 (Metabolic), and CMS4 (Mesenchymal). However, in the clinical practice only patients with MSI tumors have experienced a change in the management of their disease. Proteomics has experimented significant technical advances with the implementation of data-independent acquisition (DIA) as the gold-standard for the analysis of large cohort of patients, providing a dynamic framework of the disease and direct information about the effectors of the biological processes. The aim of this study is the characterization of the proteome of colon cancer CMS by DIA–based proteomics and expand the utility of CMS in the clinical practice. CMS were assigned and differences in the protein profiles between CMS were defined and evaluated using a Systems Biology approach. One hundred fifty-eight paraffin samples from colon cancer patients with stage II-III disease treated with adjuvant chemotherapy were analyzed. After applying quality criteria, 1,940 identified and quantified proteins were used for the analyses. CMS1 had an overexpression of proteins related to immune system, specifically neutrophils, phagocytosis and antimicrobial response, and a glycolytic profile. CMS3 had an overexpression of proteins related to metabolic pathways, while CMS2 showed an intermediate protein profile between CMS1-3, but with a characteristic profile regarding translation, adhesion, and mitochondria and metabolism biological processes. Two proteomics subtypes within CMS2 with different protein characteristics and prognosis were identified. CMS4 was the most different group with an overexpression of proteins related to angiogenesis, extracellular matrix, focal adhesion, and complement activation. In conclusion, DIA LC-MS/MS proteomics characterization of CRC CMS established new features for each CMS, such as a higher mitochondrial activity in CMS2 or an overexpression of proteins related to phagocytosis in CMS1, but also confirmed previous findings established using transcriptomics such as an overexpression of proteins related to angiogenesis in CMS4. In this CMS4 subtype, several adhesion-related proteins suggested a high metastatic profile and a possible chemoresistance that may explain the worse prognosis of this subtype. CMS1 was characterized as immune and glycolitic-active subtype, being the combination of immunotherapy and glycolytic inhibitors a possible therapeutic strategy. Additionally, two different CMS2 proteomics-based subtypes with different prognosis and possible therapeutic targets were identified. These proccesses could be used as therapeutic targets in the future.

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Small bowel carcinomas in celiac disease: transcriptomic profiling and comparison with the consensus molecular subtypes of colorectal cancers

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