Oncogene discovery in esophageal cancer through interrogation of 3D regulatory landscapes
Worldwide Cancer Research
Max Planck Institute for Molecular Genetics
Esophageal cancer is one of the most common and lethal cancers worldwide, yet currently no targeted therapeutics exists for its treatment. A critical roadblock in the development of targeted therapeutics for esophageal cancer is the lack of knowledge of the key oncogenic drivers in this cancer and the regulatory landscape that controls the expression of those genes. For example, genome-sequencing efforts of esophageal adenocarcinoma (EAC), the most frequent subtype of esophageal cancer, have revealed few frequently mutated genes to date, and those mutations have limited prognostic benefit, which suggests that mutations in non-coding DNA may play critical roles in EAC development. Gene expression programs are implemented in the three dimensional context of 3D chromosome structures, and our previous work suggests that the boundary elements of such 3D chromosome neighborhoods are frequently mutated in EAC. In this work, we propose to generate maps of the 3D regulatory landscape for multiple esophageal adenocarcinoma cells for the discovery of new oncogenic drivers. We will combine the 3D regulatory maps with whole genome sequence information to create a compressive catalog of candidate EAC driver mutations that occur in non-coding DNA elements, including chromosome neighborhood boundaries, and will use the 3D regulatory landscapes to identify oncogenes dysregulated around the mutated neighborhoods. We will functionally validate the candidate driver mutations and the new candidate oncogenes in cell line- and organoid models and using clinical information. This work will generate a functionally validated set of EAC oncogenes whose genomic sequence is otherwise intact. Results of this work will provide insights into the clinical utility of mutations disrupting chromosome neighborhoods in EAC, and facilitate the development and application of new therapeutic approaches for this common and deadly cancer.
2.1 Biological and endogenous factors