Characterizing Recurrent 18q Rearrangements In Gastric Cancer

Aims: Disease-specific chromosomal rearrangements are well known as clinical biomarkers in leukemias, lymphomas and sarcomas, with some being instrumental in the development of targeted therapy. However, few chromosomal rearrangements characteristic of epithelial tumors are known. Recent discoveries in prostate and non-small cell lung cancer suggest that epithelial malignancies may also harbor characteristic rearrangements of pathogenic significance. Thus, we aimed to investigate if recurrent rearrangements occur in gastric cancer. Methods: Seventeen gastric cancer cell lines were surveyed by spectral karyotyping and copy number analysis to identify recurrent breakpoints. Clinical tissue microarrays were probed by fluorescence in situ hybridization (FISH) assays for the most frequent breakpoints. We analyzed flow-sorted rearranged chromosomes using high resolution copy number analysis, deep sequencing and custom tiling array CGH to locate the translocation junctions. Quantitative genomic and RT-PCR, and FISH using fosmid clones further confirmed breakpoint positions. Results: Breakpoints at 18q were the most prevalent among 45 recurrent breakpoints, being present in six of 17 gastric cancer cell lines. 18q12.2 and 18q22.2 breakpoints were present in 44% and 22%, respectively, of 99 primary gastric cancers. These breakpoints were absent in breast, colorectal, hepatocellular, pancreatic and prostate cancers. However, the 18q12.2 breakpoint was present in 47% of lung adenocarcinomas. 18q monosomy was common in intestinal metaplasia. Custom-designed FISH assays further identified translocation partners, t(6;18), t(8;18) and t(9;18) in 4%, 5% and 10%, respectively, of 99 primary gastric cancers. Sharp transitions in genome copy number of flow-sorted translocated chromosomes mapped 18q breakpoints with greater precision, and were confirmed by deep sequencing as well as custom tiling array. The 18q22.2 breakpoint mapped to intron 4 of DOK6. The 18q12.2 breakpoint mapped to an intergenic region, 146kb from an enhancer (element 851, Vista Enhancer browser). Conclusion: This is the first documentation of recurrent chromosomal rearrangements in clinical gastric cancer. Ongoing work is focused on understanding what functional consequences, if any, are associated with these signature translocations. Acknowledgements: We thank Dr. Sun Young Rha (Yonsei Cancer Center, South Korea) for the kind gift of seven gastric cancer cell lines, Dr. Nigel Carter and Ms Bee Ling Ng (Wellcome Trust Sanger Institute, United Kingdom) for chromosome flow sorting, Dr. Steve Rozen and Dr. Ioana Cutcutache (Duke-NUS Medical School, Singapore) for assistance with sequence analysis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3823. doi:10.1158/1538-7445.AM2011-3823