Format

Send to

Choose Destination
Cell Rep. 2015 Jul 14;12(2):272-85. doi: 10.1016/j.celrep.2015.06.020. Epub 2015 Jul 2.

Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.

Author information

1
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore; The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore.
2
Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
3
Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
4
Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
5
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
6
National Key Laboratory of Crop Genetic Improvement, Center for Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
7
Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore; School of Computing, National University of Singapore, Singapore 117417, Singapore.
8
The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
9
Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore.
10
Personal Genomic Solutions, Genome Institute of Singapore, Singapore 138672, Singapore.
11
Research Computing, Genome Institute of Singapore, Singapore 138672, Singapore.
12
Genome Technology and Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
13
Département de Biologie, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
14
The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; National University Health System, Singapore 119228, Singapore.
15
Personal Genomic Solutions, Genome Institute of Singapore, Singapore 138672, Singapore; Genome Technology and Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
16
The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; National University Health System, Singapore 119228, Singapore.
17
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore; The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore; Duke-NUS Graduate Medical School, Singapore 169857, Singapore; Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
18
Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Singapore; Department of Physiology, National University of Singapore, Singapore 117597, Singapore. Electronic address: hunziker@imcb.a-star.edu.sg.
19
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA. Electronic address: yijun.ruan@jax.org.
20
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore; The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore. Electronic address: hillmer@gis.a-star.edu.sg.

Abstract

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.

PMID:
26146084
DOI:
10.1016/j.celrep.2015.06.020
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center