miRNA profiling of small intestinal neuroendocrine tumors defines novel molecular subtypes and identifies miR-375 as a biomarker of patient survival
Journal article, 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.

Author

Yvonne Arvidsson

University of Gothenburg

Anna Rehammar

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

Anders Bergström

University of Gothenburg

Ellinor Andersson

University of Gothenburg

Gülay Altiparmak

University of Gothenburg

Christina Swärd

Sahlgrenska Academy

Bo Wängberg

Sahlgrenska Academy

Erik Kristiansson

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

Ola Nilsson

University of Gothenburg

Modern Pathology

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

Vol. 31 8 1302-1317

Subject Categories

Clinical Laboratory Medicine

Medical Genetics

Cancer and Oncology

DOI

10.1038/s41379-018-0010-1

More information

Latest update

9/10/2018