Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.
By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.
Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043).
Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.
SOURCE: American Gastroenterological Association
Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.”
These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.
The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.