miRNA profiling of small intestinal neuroendocrine tumors defines novel molecular subtypes and identifies miR-375 as a biomarker of patient survival
Artikel i vetenskaplig tidskrift, 2018

The aim of this study was to define the miRNA profile of small intestinal neuroendocrine tumors and to search for novel molecular subgroups and prognostic biomarkers. miRNA profiling was conducted on 42 tumors from 37 patients who underwent surgery for small intestinal neuroendocrine tumors. Unsupervised hierarchical clustering analysis of miRNA profiles identified two groups of tumor metastases, denoted cluster M1 and M2. The smaller cluster M1 was associated with shorter overall survival and contained tumors with higher grade (WHO grade G2/3) and multiple chromosomal gains including gain of chromosome 14. Tumors of cluster M1 had elevated expression of miR-1246 and miR-663a, and reduced levels of miR-488-3p. Pathway analysis predicted Wnt signaling to be the most significantly altered signaling pathway between clusters M1 and M2. Analysis of miRNA expression in relation to tumor proliferation rate showed significant alterations including downregulation of miR-137 and miR-204-5p in tumors with Ki67 index above 3%. Similarly, tumor progression was associated with significant alterations in miRNA expression, e.g. higher expression of miR-95 and miR-210, and lower expression of miR-378a-3p in metastases. Pathway analysis predicted Wnt signaling to be altered during tumor progression, which was supported by decreased nuclear translocation of β-catenin in metastases. Survival analysis revealed that downregulation of miR-375 was associated with shorter overall survival. We performed in situ hybridization on biopsies from an independent cohort of small intestinal neuroendocrine tumors using tissue microarrays. Expression of miR-375 was found in 578/635 (91%) biopsies and survival analysis confirmed that there was a correlation between downregulation of miR-375 in tumor metastases and shorter patient survival. We conclude that miRNA profiling defines novel molecular subgroups of metastatic small intestinal neuroendocrine tumors and identifies miRNAs associated with tumor proliferation rate and progression. miR-375 is highly expressed in small intestinal neuroendocrine tumors and may be used as a prognostic biomarker.

Författare

Yvonne Arvidsson

Göteborgs universitet

Anna Rehammar

Chalmers, Matematiska vetenskaper, Tillämpad matematik och statistik

Anders Bergström

Göteborgs universitet

Ellinor Andersson

Göteborgs universitet

Gülay Altiparmak

Göteborgs universitet

Christina Swärd

Sahlgrenska akademin

Bo Wängberg

Sahlgrenska akademin

Erik Kristiansson

Chalmers, Matematiska vetenskaper, Tillämpad matematik och statistik

Ola Nilsson

Göteborgs universitet

Modern Pathology

0893-3952 (ISSN) 1530-0285 (eISSN)

Vol. 31 8 1302-1317

Ämneskategorier

Klinisk laboratoriemedicin

Medicinsk genetik

Cancer och onkologi

DOI

10.1038/s41379-018-0010-1

Mer information

Senast uppdaterat

2018-09-10