AsianScientist (Jul. 20, 2015) – A Frankenstein gene—formed by the fusion of two genes—has been implicated in Asian gastric cancers. The study documenting these findings has been published in Cell Reports.
Structural changes of chromosomes (genome rearrangements), can result in gene fusions with properties that can cause cancer. The three-dimensional organisation of the genome, known as the chromatin structure, plays a role for the generation of rearrangements.
In the present study, researchers from Singapore’s Agency for Science, Technology and Research (A*STAR)’s Genome Institute of Singapore (GIS) and Institute of Molecular and Cell Biology (IMCB), together with colleagues from the National University Health System (NUHS) and Tan Tock Seng Hospital, discovered that the fusion of two genes, CLDN18 and ARHGAP26, gives rise to the destruction of the stomach surface barrier, resulting in gastric acids affecting the stomach tissues. Moreover, CLDN18-ARHGAP26 also hampers wound-healing.
Using a technique known as DNA paired-end-tag (DNA-PET) whole genome sequencing, GIS scientists analysed 15 gastric cancers (GCs) from Southeast Asians, and observed that rearrangements were enriched in regions of active genes. They subsequently screened 100 GCs for certain fusion genes that were discovered in the 15 GCs.
Through the sequencing, the scientists identified seven hotspots across the genome which had many rearrangements as well as 136 gene fusions. In three out of the 100 GC cases, they found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding an RHOA inhibitor.
The functions of both genes are important for a tight inner surface (epithelium) of the stomach. Epithelial cell lines expressing the fused genes CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT), a property seen in invasive cancer cells.
Fusion positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix-adhesion, retarded wound healing and inhibition of RHOA. Gain of invasion, a property that contributes to metastases, was seen in cancer cell lines expressing the fusion.
Overall, the scientists suggest that CLDN18-ARHGAP26 causes epithelial disintegration that leads to leakage of gastric acids, and the fusion might contribute to invasiveness of tumors once a cell is transformed.
Dr. Walter Hunziker, deputy director of IMCB and co-senior author of the publication, added, “CLDN18 is a critical component of the gastric epithelial barrier. Fusion of ARHGAP26 to CLDN18 not only interferes with the tethering of CLDN18 to the actin cytoskeleton, but could also affect the actin cytoskeleton by inhibiting RHOA at the wrong location, thereby compromising barrier integrity. The resulting inflammation and gastritis are well known risk factors for gastric cancer.”
“Gastric cancer has a high incidence in Asia, and it is important for Asian scientists to improve our understanding of diseases which are important in our population,” said deputy chief executive (Academic Enterprise) at NUHS, associate professor Yeoh Khay Guan.
The article can be found at: Yao et al. (2015) Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.
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Source: A*STAR.
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