Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours.
BMJ Open Gastroenterol
; 8(1)2021 11.
Article
em En
| MEDLINE
| ID: mdl-34750164
ABSTRACT
OBJECTIVE:
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) encompass a diverse group of neoplasms that vary in their secretory products and in their location within the gastrointestinal tract. Their prevalence in the USA is increasing among all adult age groups.AIM:
To identify the possible derivation of GEP-NETs using genome-wide analyses to distinguish small intestinal neuroendocrine tumours, specifically duodenal gastrinomas (DGASTs), from pancreatic neuroendocrine tumours.DESIGN:
Whole exome sequencing and RNA-sequencing were performed on surgically resected GEP-NETs (discovery cohort). RNA transcript profiles available in the Gene Expression Omnibus were analysed using R integrated software (validation cohort). Digital spatial profiling (DSP) was used to analyse paraffin-embedded GEP-NETs. Human duodenal organoids were treated with 5 or 10 ng/mL of tumor necrosis factor alpha (TNFα) prior to qPCR and western blot analysis of neuroendocrine cell specification genes.RESULTS:
Both the discovery and validation cohorts of small intestinal neuroendocrine tumours induced expression of mesenchymal and calcium signalling pathways coincident with a decrease in intestine-specific genes. In particular, calcium-related, smooth muscle and cytoskeletal genes increased in DGASTs, but did not correlate with MEN1 mutation status. Interleukin 17 (IL-17) and tumor necrosis factor alpha (TNFα) signalling pathways were elevated in the DGAST RNA-sequencing. However, DSP analysis confirmed a paucity of immune cells in DGASTs compared with the adjacent tumour-associated Brunner's glands. Immunofluorescent analysis showed production of these proinflammatory cytokines and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) by the tumours and stroma. Human duodenal organoids treated with TNFα induced neuroendocrine tumour genes, SYP, CHGA and NKX6.3.CONCLUSIONS:
Stromal-epithelial interactions induce proinflammatory cytokines that promote Brunner's gland reprogramming.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
/
Gastrinoma
/
Tumores Neuroendócrinos
/
Neoplasias Intestinais
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
/
Humans
Idioma:
En
Revista:
BMJ Open Gastroenterol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos