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Updated: Oct 16, 2025
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
OLFM4-RET fusion is an oncogenic driver in small intestine adenocarcinoma
Wenli Liu1, Hongzhen Li1, Wulin Aerbajinai1
1Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Abstract:
Small intestine adenocarcinoma is a rare intestinal malignancy with distinct clinical, pathological, and molecular characteristics. Recently, a fusion of the intestinal stem-cell marker olfactomedin 4 (OLFM4) and the proto-oncogene RET has been identified in a small intestine adenocarcinoma patient. Here we investigated the biological effects of OLFM4-RET fusion and whether it can initiate tumorigenesis in small intestine. OLFM4 expression was found to be frequently lost or reduced in human small intestine adenocarcinoma, and its downregulation correlated with high tumor grade and advanced tumor stage. Expression of OLFM4-RET fusion-induced cellular transformation in HEK293 cells and blocked RET-induced inhibition of colony growth in HuTu 80 small intestine adenocarcinoma cells. Further, expression of OLFM4-RET activated the RAS-RAF-MAPK and STAT3 cell signaling pathways in both HEK293 cells and HuTu 80 cells. OLFM4-RET expression in HEK293 cells upregulated multiple families of genes related to carcinogenesis, cancer progression, and metastasis. Targeted expression of OLFM4-RET in the small intestine led to the development of hyperplasia, adenoma, or adenocarcinoma in transgenic mice. Our study suggests that OLFM4-RET is an oncogenic driver of small intestine tumorigenesis. Therefore, the small intestine adenocarcinoma patients with OLFM4-RET fusion may benefit from treatment with RET kinase inhibitor.
Insights
The OLFM4-RET fusion drives small intestine adenocarcinoma by activating cancer pathways and promoting tumor growth. This fusion may indicate patients who could benefit from RET kinase inhibitor therapy.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- Small intestine adenocarcinoma is a rare cancer with unique features.
- The OLFM4-RET fusion gene was recently found in a patient with this cancer.
Purpose of the Study:
- To investigate the biological impact of the OLFM4-RET fusion.
- To determine if OLFM4-RET can initiate small intestine tumors.
Main Methods:
- Assessed OLFM4 expression in human tumors.
- Expressed OLFM4-RET in cell lines (HEK293, HuTu 80) and transgenic mice.
- Analyzed cellular signaling pathways (RAS-RAF-MAPK, STAT3) and gene expression.
- Observed tumor development in mice.
Main Results:
- OLFM4 expression is reduced in small intestine adenocarcinoma, correlating with advanced stages.
- OLFM4-RET induced cell transformation and activated oncogenic signaling pathways.
- In mice, OLFM4-RET expression led to hyperplasia, adenoma, and adenocarcinoma development.
Conclusions:
- OLFM4-RET acts as an oncogenic driver in small intestine tumorigenesis.
- Small intestine adenocarcinoma patients with OLFM4-RET fusion may respond to RET kinase inhibitors.
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