Clustering of molecular alterations in gastroesophageal carcinomas

Gene expression levels are regulated at many levels. Integration of genome-wide analyses for the study of DNA and RNA provides a unique tool to detect genetic alterations in the cancer genome. In this study, we generated and integrated DNA amplification data from comparative genomic hybridization (CGH) and serial analyses of gene expression (SAGE) in order to obtain a molecular profile of gastroesophageal junction (GEJ) carcinomas. DNA amplifications mapped to specific chromosomal regions and were frequently seen at 1q, 4q, 5q, 6p, 7p, 8q, 17q, and 20q. Using SAGE, we obtained over 156,432 tags from GEJ adenocarcinomas and normal gastric mucosa. These tags were assigned to UniGene clusters. Chromosomal positions for overexpressed genes were obtained to produce a GEJ carcinoma transcriptome map. A total of 123 genes was significantly overexpressed (more than fivefold; P <.01) in one or more SAGE libraries. This gene overexpression map was integrated and compared to the chromosomal CGH ideogram. Several chromosomal arms that had frequent DNA amplifications showed frequent gene expression alterations such as chromosomes 1 (15 genes), 2 (9 genes), 6 (6 genes), 11 (6 genes), 12 (8 genes), and 17 (13 genes). Despite the relatively large DNA amplification regions, overexpressed genes frequently mapped and clustered to small chromosomal regions at early-replicating (Giemsa light) bands such as 1q21.3 (nine genes), 6p21.3 (five genes), and 17q21 (eight genes). These results provide a comprehensive tool to search for DNA amplifications and overexpressed genes in GEJ carcinoma. The observed phenomenon of the presence of large amplification areas, yet clustering of overexpressed genes to relatively small loci, may suggest a high organization of chromatin and cancer-related genes in the nucleus.