Purpose: Gastric cancer, the second leading cause of cancer death worldwide, has been little studied compared with other cancers that impose similar burdens on public health. Our goal is to assess loss of heterozygosity (LOH) and hemizygous deletion across a large series of gastric adenocarcinomas using the most sensitive and comprehensive method currently available.
Experimental design: We used high-density single-nucleotide-polymorphism microarrays that assay genotype and copy number at 906,600 sites and analyzed the results to determine patterns of LOH and hemizygous deletion in 77 gastric adenocarcinomas. We investigated whether “STOP” genes - genes that tend to impede proliferation - are associated with hemizygous deletion. We also analyzed the extent to which hemizygous deletion affected CYCLOPS (Copy number alterations Yielding Cancer Liabilities Owing to Partial losS) genes - genes that may be attractive targets for therapeutic inhibition when hemizygously deleted.
Results: We found that LOH is pervasive: on average 27% of each tumor genome is subject to LOH, and > 98% of single nucleotide polymorphisms assayed were subject to LOH in at least 10% of tumors. Furthermore, 26% of LOH was due to hemizygous deletion, and STOP genes were significantly associated with regions of frequent hemizygous deletion; on average, 61 STOP genes were hemizygously deleted per tumor. Furthermore, on average, 4.65 CYCLOPS genes were hemizygously deleted per tumor, and 54.5% of the tumors had at least one CYCLOPS gene deleted.
Conclusions: These findings suggest that hemizygous deletion of anti-proliferative STOP genes contributes substantially to gastric carcinogenesis. Furthermore, the presence of several hemizygously deleted CYLOPS genes in some tumors suggests potential therapeutic targets in these tumors.
Citation Format: Ioana Cutcutache, Alice Yingting Wu, John R. McPherson, Zhengdeng Lei, Niantao Deng, Wai Keong Wong, Khee Chee Soo, Weng Hoong Chan, London Lucien Ooi, Roy E. Welsch, Patrick Tan, Steven G. Rozen. Gastric adenocarcinomas show pervasive loss of heterozygosity and enrichment for “STOP” genes in regions of hemizygous deletion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5168. doi:10.1158/1538-7445.AM2014-5168