Researchers identify recurrent fusion genes responsible for gastric cancer initiation.


Worldwide, close to a million cases of gastric cancers are diagnosed each year with some of the world’s highest incidence rates are in Asia (particularly in Korea, Japan and China).  Now, researchers at The Jackson Laboratory, the Genome Institute of Singapore and other institutions state that they have identified five previously unknown recurrent fusion genes, one of which appears to lead to cellular changes involved in acute gastritis and cancer.  The opensource study is published in the journal Cell Reports.

Previous studies show that recurrent fusion genes are separate genes fused together to produce a single protein product. The most famous example of a fusion gene is the BCR-ABL protein, nicknamed the Philadelphia chromosome, which directly causes about 90 percent of chronic myelogenous leukemia cases.  Profound chromosomal disruptions and rearrangements are found in many cancers. As a result, simple linear sequencing of tumour genomes fails to capture all of the genomic perturbations that contribute to cancer initiation, maintenance and metastasis. Structural variants, copy number variants, inversions and fusion gene products which can all contribute to malignancy, are difficult to find using standard array-based hybridization and next-generation sequencing protocols.

The current study followed the gastric cancers of 15 Southeast Asian patients.  The researchers used a DNA-PET (paired-end-tag) sequencing method which can detect and characterize genomic structural rearrangements.  The new method was utilised to analyze the gastric cancer patient cells, and identified five recurrent fusion genes. The data findings show that one of the fusions combined CLDN18, which is essential for tight junctions in the stomach that prevent leakage, and ARHGAP26, which is involved in cell adhesion.

Working in both normal and transformed (cancerous) cell lines, the team observed that CLDN18-ARHGAP26 expression changed the characteristic of both cell types significantly. The results show that the cells adhered poorly to each other and to the extracellular matrix, increasing susceptibility to damage and diminishing healing.

The lab state that the changes point to an increased indication for acute gastritis, a risk factor for gastric cancer. They go on to add that the CLDN18-ARHGAP26 expression also promotes invasive tendencies in the cells, which aids in cancer progression once the cancer initiates.

The researchers surmise that this work exemplifies the complexity of cancer genomes undergoing genomic rearrangement.  They go on to conclude that the work also highlights the need for developing new sophisticated genomic analysis approaches to ultimately provide critical insights into cancer progression.

Source:  The Jackson Laboratory

Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). 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 was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H+ leakage, and the fusion might contribute to invasiveness once a cell is transformed.  Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.  Hillmer et al 2015.

Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). 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 was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H+ leakage, and the fusion might contribute to invasiveness once a cell is transformed. Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity. Hillmer et al 2015.

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