Small-bowel carcinomas associated with celiac disease: transcriptomic profiling shows predominance of microsatellite instability-immune and mesenchymal subtypes

• Published in: Virchows Archiv : an international journal of pathology 2020-05, Vol.476 (5), p.711-723
• Main Authors: Rizzo, Francesca, Vanoli, Alessandro, Sahnane, Nora, Cerutti, Roberta, Trapani, Davide, Rinaldi, Antonio, Sellitto, Assunta, Ciacci, Carolina, Volta, Umberto, Villanacci, Vincenzo, Calabrò, Antonio, Arpa, Giovanni, Luinetti, Ombretta, Paulli, Marco, Solcia, Enrico, Di Sabatino, Antonio, Sessa, Fausto, Weisz, Alessandro, Furlan, Daniela
• Format: Article
• Language: English
• Subjects: Angiogenesis; Apoptosis; Autoimmune diseases; Cancer; CD3 antigen; CD8 antigen; Celiac disease; Cell cycle; Colorectal cancer; Colorectal carcinoma; Complement activation; Consortia; CpG islands; DNA methylation; Gene expression; Growth factors; Histochemical analysis; Infiltration; Inflammation; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Microsatellite instability; Natural killer cells; Original Article; Pathogenesis; Pathology; Phenotypes; Proteasomes; Quality in Pathology; Ribonucleic acid; Risk analysis; Risk factors; RNA; Sensitivity analysis; Signatures; Small intestine; Stroma; Transcription; Transcriptomics; Transforming growth factor-b; Tumors
• ISSN: 0945-6317; 1432-2307
• DOI: 10.1007/s00428-019-02675-w

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.