Cell Reports (Jul 2015)

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

  • Fei Yao,
  • Jaya P. Kausalya,
  • Yee Yen Sia,
  • Audrey S.M. Teo,
  • Wah Heng Lee,
  • Alicia G.M. Ong,
  • Zhenshui Zhang,
  • Joanna H.J. Tan,
  • Guoliang Li,
  • Denis Bertrand,
  • Xingliang Liu,
  • Huay Mei Poh,
  • Peiyong Guan,
  • Feng Zhu,
  • Thushangi Nadeera Pathiraja,
  • Pramila N. Ariyaratne,
  • Jaideepraj Rao,
  • Xing Yi Woo,
  • Shaojiang Cai,
  • Fabianus H. Mulawadi,
  • Wan Ting Poh,
  • Lavanya Veeravalli,
  • Chee Seng Chan,
  • Seong Soo Lim,
  • See Ting Leong,
  • Say Chuan Neo,
  • Poh Sum D. Choi,
  • Elaine G.Y. Chew,
  • Niranjan Nagarajan,
  • Pierre-Étienne Jacques,
  • Jimmy B.Y. So,
  • Xiaoan Ruan,
  • Khay Guan Yeoh,
  • Patrick Tan,
  • Wing-Kin Sung,
  • Walter Hunziker,
  • Yijun Ruan,
  • Axel M. Hillmer

DOI
https://doi.org/10.1016/j.celrep.2015.06.020
Journal volume & issue
Vol. 12, no. 2
pp. 272 – 285

Abstract

Read online

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.