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
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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