Genomic instability appears to play an important role in most human cancers. To more fully characterize genomic instability and assess its effect on gene expression in esophageal squamous cell carcinoma (ESCC), we examined loss of heterozygosity (LOH), copy number (CN) loss, and CN gain, as well as gene expression, using genome-wide methods in cases from a high-risk region of China.


Micro-dissected tumor and matched germ-line DNA from 30 ESCC patients from Shanxi Province, PR China who underwent surgical resection were tested using the Affymetrix GeneChip Human Mapping 500K array set and frequencies of LOH and CN alterations were determined. Matched micro-dissected tumor/non-tumor samples were also tested for RNA expression with Affymetric Human Genome U133A 2.0 arrays on a subset of 17 of these patients.


Genomic instability measures varied widely among cases and separated them into two distinct groups: a high frequency instability group (two-thirds of all cases with 1 or more instability measure >10%) and a low frequency instability group (one-third of cases with no instability measures >10%). Genomic instability also varied widely across chromosomal arms, with the highest frequency of LOH on 9p (33% of informative SNPs), of CN loss on 3p (33%), and of CN gain on 3q (48%). Genome-wide LOH measured with the 500K chip produced remarkably similar frequency rankings for chromosome arms as previous less-dense genome-wide scans that used microsatellites or the 10K SNP chip, although absolute frequencies were reduced. Twelve regions with particularly high CN gain were identified, including six on 3q, one on 7q, four on 8q, and one on 11q. The most gene-rich of these CN gain regions was 11q13.1-13.4, where we identified 26 genes with frequent CN gain which also had RNA expression data available. CN gain was significantly correlated with increased RNA expression in over 80% of these genes.


Genomic instability patterns show two heterogeneous groups of ESCC cases; the high-frequency instability group may harbor germ-line variants or acquired somatic mutations in genes that maintain genomic stability. Genome-wide studies from this high-risk population show a consistent pattern of high LOH on selected chromosome arms which are targets in searching for loss-of-function genes involved in ESCC. Our findings demonstrate the potential utility of combining CN and gene expression data to screen for genes involved in esophageal carcinogenesis. Future studies should combine results in tumors with germ-line genotypes to find functional changes, and determine if these changes are associated with genetic susceptibility to ESCC or might serve as early detection markers.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B1.

Seventh AACR International Conference on Frontiers in Cancer Prevention Research-- Nov 16-19, 2008; Washington, DC