We have examined DNA from four human esophageal carcinoma cell lines and 50 primary esophageal carcinomas obtained from China, Italy, and France for amplification of the cyclin Dl gene. We also examined 36 of these 50 carcinomas for expression of the cydin Dl and retinoblastoma (RB) proteins by immunohistochemistry. We found a 3-to 10-fold amplification of the cyclin Dl INT2,, and loss of heterozygosity of the tumor suppressor genes RB (9), p53 (10-12), MCC (13) and APC (13). Point mutations in the p53 gene occur in about 40% of esophageal cancers (10-12). However, activation of RAS oncogenes by point mutation appears to be a very rare event in this type of cancer (12,(14)(15)(16). Despite the fact that amplification of the HSTI and INT2 genes on chromosome 11q13 has been found in about 20-50% ofesophageal cancers, little or no expression of these two genes has been detected in the corresponding cells (6)(7)(8). These findings suggest that an additional gene(s) at the chromosome 11q13 locus is involved in the development of esophageal cancer. These considerations attracted our interest in a recent report thatThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. the cyclin Dl gene had been mapped to the chromosome 11q13 locus close to the INT2 and HSTI genes (17).Cyclins form a family of proteins that complex with cyclindependent protein kinases (CDKs) to govern key transitions in the cell cycle (for review, see refs. 18 and 19) Cyclin Dl was isolated as a gene that is rearranged in parathyroid adenomas (PRADI) and certain B-cell leukemias (BCL-J) (17,20). It also complements a Saccharomyces cerevisiae strain that is mutant in three known Gl cyclins (21, 22) and is induced in the late G1 phase following the treatment of a growth-arrested macrophage cell line with colony-stimulating factor 1 (23). The product of the cyclin Dl gene is expressed at high levels and forms a complex with a CDK during the G1 phase of the cell cycle in sychronized cells (23). In a recent study we detected amplification of the cyclin Dl gene in about 25% of primary esophageal tumors from China (24).The RB gene, which is located on chromosome 13q14, was the first tumor suppressor gene to be isolated. Loss of heterozygosity and loss ofexpression ofthe RB gene are seen during the development of retinoblastoma (RB) and several other types of human cancers (25). The product of the RB gene is a 110-kDa nuclear phosphoprotein. This protein is hypophosphorylated during the G1 phase and hyperphosphorylated in the S, G2, and M phases of the cell cycle. It is thought that this phosphorylation blocks an inhibitory function ofthe RB protein on progression through the later phases of the cell cycle (26). Alternatively, oncoproteins encoded by certain DNA tumor viruses can bind to the RB protein and block its inhibitory function (26). In vitro studies demonstrate that several serine and th...

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