Small-bowel carcinomas associated with celiac disease: transcriptomic profiling shows predominance of microsatellite instability-immune and mesenchymal subtypes
Autor: | Alessandro Vanoli, Francesca Rizzo, Antonio Calabrò, Marco Paulli, Fausto Sessa, Vincenzo Villanacci, Roberta Cerutti, Assunta Sellitto, Antonio Di Sabatino, Ombretta Luinetti, Antonio Rinaldi, Alessandro Weisz, Nora Sahnane, Giovanni Arpa, Umberto Volta, Daniela Furlan, Enrico Solcia, Carolina Ciacci, Davide Trapani |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Adult Male Colorectal cancer Population RNA-sequencing Celiac disease Small-bowel carcinoma Transcriptomic profiling Biology Pathology and Forensic Medicine Natural killer cell Pathogenesis Cohort Studies 03 medical and health sciences 0302 clinical medicine Risk Factors Intestinal Neoplasms Intestine Small Carcinoma medicine Humans Intestinal Mucosa education Molecular Biology Aged education.field_of_study CpG Island Methylator Phenotype Sequence Analysis RNA Gene Expression Profiling Microsatellite instability Computational Biology Cell Biology General Medicine DNA Methylation Middle Aged medicine.disease Celiac Disease 030104 developmental biology medicine.anatomical_structure Phenotype 030220 oncology & carcinogenesis Mutation Cancer research CpG Islands Female Microsatellite Instability Transcriptome CD8 |
Zdroj: | Virchows Archiv : an international journal of pathology. 476(5) |
ISSN: | 1432-2307 |
Popis: | Celiac disease (CD) is a risk factor for developing small-bowel carcinoma with a 14-fold higher risk compared with general population. As small-bowel carcinomas associated with CD (CD-SBCs) are extremely rare, very few molecular data are available about their pathogenesis, and information about their transcriptomic profiling is lacking. We generated RNA-seq data on 13 CD-SBCs, taken from the largest well-characterized series published so far, collected by the Small Bowel Cancer Italian Consortium, and compared the tumor transcriptional signatures with the four Consensus Molecular Subtypes (CMS) of colorectal carcinoma by applying the "CMS classifier." CpG Island Methylator Phenotype (CIMP) was evaluated using methylation-sensitive multiple ligation-dependent probe amplification. Up to 12 of 13 cancers fell within the two main subtypes exhibiting high immune and inflammatory signatures, i.e., subtypes 1 and 4. The first and predominant subset was commonly microsatellite unstable, and exhibited CIMP and high CD3+ and CD8+ T cell infiltration. Moreover, it showed increased expression of genes associated with T helper 1 and natural killer cell infiltration, as well as upregulation of apoptosis, cell cycle progression, and proteasome pathways. By contrast, cancers falling in subtype 4 showed prominent transforming growth factor-β activation and were characterized by complement-associated inflammation, matrix remodeling, cancer-associated stroma production, and angiogenesis. Parallel histologic and histochemical analysis confirmed such tumor subtyping. In conclusion, two molecular subtypes have been consistently identified in our series of CD-SBCs, a microsatellite instability-immune and a mesenchymal subtype, the former likely associated with an indolent and the latter with a worse tumor behavior. |
Databáze: | OpenAIRE |
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