Genomics and Mechanisms of Esophageal Carcinogenesis

在美国，大约有330万成年人患有巴雷特食管（BE）。一小部分患者

1 Barrett's esophagus (BE) affects about 3.3 million adults in the United States1. A small subset of patients with 2 BE may sequentially progress from intestinal metaplasia (BIM-P) to low-grade dysplasia (LGD), high-grade 3 dysplasia (HGD) and esophageal adenocarcinoma (EAC). The incidence of EAC has increased greater than 5- 4 fold over the past 4 decades in the United States2. Patients with BIM without dysplasia have a much lower 5 EAC risk than those with high-grade dysplasia. For effective health care, identification of molecular markers 6 that predict progression of BIM to HGD/EAC is highly desirable, as BIM-P may be monitored and aggressively 7 treated to inhibit progression to EAC. Our laboratory and others have identified genomic alterations that may 8 drive HGD/EAC development, including point mutations 6 and copy number changes. We found frequent (50%) 9 losses in chromosome 9p areas containing CDKN2A/p16 in BIM-P but not in non-progressors. Inactivation of 10 CDKN2A/p16 by methylation is a frequent event in BE progression to HGD/EAC7-9. Molecular 11 genomic/epigenomic testing of surveillance biopsies may identify candidate high-risk BIM patients for closer 12 surveillance and chemoprevention of HGD/EAC. We propose a combination of demethylating agents to 13 reverse CpG methylation in p16 and other genes that may contribute to neoplastic progression with anti- 14 inflammatory drugs, which have been shown to reduce HGD/EAC development 13 14. Our hypothesis is that 15 the CDKN2A gene product p16 is key in determining disease progression in a large number of those 16 BE patients who develop dysplasia/EAC and that detection of CDKN2A/p16 alterations and/or 17 molecular genomic, epigenetic and expression alterations that result from CDKN2A/p16 inactivation 18 may be used to direct early therapeutic intervention to prevent EAC development. We will address this 19 hypothesis in three specific aims. Aim 1: To characterize the global transcriptomic alterations that result 20 from CDKN2A/p16 genomic and epigenetic inactivation, leading to evasion from senescence and increased 21 proliferation, in patients with BE who progress to HGD/EAC. These alterations will permit the identification of 22 molecular pathways, potential novel treatment targets and biomarkers of high-risk BIM patients, who are 23 candidates for intervention therapy (such as demethylating and anti-inflammatory drugs) to prevent HGD/EAC. 24 Aim 2: To investigate the role of CDKN2A/p16 in esophageal dysplasia and adenocarcinoma development and 25 progression in mouse models of esophageal Barrett's-like metaplasia progressing to HGD/EAC. Aim 3: To 26 investigate the effect of demethylating and anti-inflammatory drugs in the context of active and inactive 27 CDKN2A/p16, in the development of esophageal dysplasia and adenocarcinoma in the established mouse 28 models. To characterize the comprehensive transcriptomic alterations that result from CDKN2A/p16 29 inactivation, in mice with BE-like lesions that progress to HGD/EAC under effect of treatment vs. no treatment. 30 Transcriptomic mouse data will be compared with data from human tissues tested in aim 1.