title: Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.
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.
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore; The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Fei
authors.initials: F
authors.lastname: Yao
authors.affiliation: Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
authors.forename: Jaya P
authors.initials: JP
authors.lastname: Kausalya
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore; The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Yee Yen
authors.initials: YY
authors.lastname: Sia
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore; The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Audrey S M
authors.initials: AS
authors.lastname: Teo
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Wah Heng
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
authors.forename: Alicia G M
authors.initials: AG
authors.lastname: Ong
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Zhenshui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Joanna H J
authors.initials: JH
authors.lastname: Tan
authors.affiliation: National Key Laboratory of Crop Genetic Improvement, Center for Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Denis
authors.initials: D
authors.lastname: Bertrand
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Xingliang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Huay Mei
authors.initials: HM
authors.lastname: Poh
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore; School of Computing, National University of Singapore, Singapore 117417, Singapore.
authors.forename: Peiyong
authors.initials: P
authors.lastname: Guan
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore; The Singapore Gastric Cancer Consortium, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Thushangi Nadeera
authors.initials: TN
authors.lastname: Pathiraja
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Pramila N
authors.initials: PN
authors.lastname: Ariyaratne
authors.affiliation: Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore.
authors.forename: Jaideepraj
authors.initials: J
authors.lastname: Rao
authors.affiliation: Personal Genomic Solutions, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Xing Yi
authors.initials: XY
authors.lastname: Woo
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Shaojiang
authors.initials: S
authors.lastname: Cai
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Fabianus H
authors.initials: FH
authors.lastname: Mulawadi
authors.affiliation: Personal Genomic Solutions, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Wan Ting
authors.initials: WT
authors.lastname: Poh
authors.affiliation: Research Computing, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Veeravalli
authors.affiliation: Research Computing, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Chee Seng
authors.initials: CS
authors.lastname: Chan
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Seong Soo
authors.initials: SS
authors.lastname: Lim
authors.affiliation: Genome Technology and Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: See Ting
authors.initials: ST
authors.lastname: Leong
authors.affiliation: Genome Technology and Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Say Chuan
authors.initials: SC
authors.lastname: Neo
authors.affiliation: Genome Technology and Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Poh Sum D
authors.initials: PS
authors.lastname: Choi
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Elaine G Y
authors.initials: EG
authors.lastname: Chew
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Nagarajan
authors.affiliation: Département de Biologie, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
authors.forename: Pierre-Étienne
authors.initials: PÉ
authors.lastname: Jacques
authors.affiliation: 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.
authors.forename: Jimmy B Y
authors.initials: JB
authors.lastname: So
authors.affiliation: Personal Genomic Solutions, Genome Institute of Singapore, Singapore 138672, Singapore; Genome Technology and Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Ruan
authors.affiliation: 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.
authors.forename: Khay Guan
authors.initials: KG
authors.lastname: Yeoh
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore; School of Computing, National University of Singapore, Singapore 117417, Singapore.
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Sung
authors.affiliation: 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.
authors.forename: Walter
authors.initials: W
authors.lastname: Hunziker
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA. Electronic address: yijun.ruan@jax.org.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: 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.
authors.forename: Axel M
authors.initials: AM
authors.lastname: Hillmer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002966:Clathrin / Q000494:pharmacology; D057167:Claudins / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D004705:Endocytosis / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D061985:Madin Darby Canine Kidney Cells; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C115971:ARHGAP26 protein, human; C486683:CLDN18 protein, human; D002966:Clathrin; D057167:Claudins; D020690:GTPase-Activating Proteins; D015514:Oncogene Proteins, Fusion; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein