Insights into the origin of esophageal cancer could boost early detection efforts

Barrett’s esophagus is a complication of chronic heartburn and a known risk factor for esophageal cancer. Now scientists at the University of Cambridge have found a subtype of this cancer that always starts with Barrett’s—and unlocked the steps by which the transformation to cancer starts. They believe their findings could improve the early detection of esophageal cancer.

The researchers discovered that cells at the top of the stomach can take on the properties of intestinal cells in the formation of Barrett's, and that this change in identity is controlled by two genes, MYC and HNF4A. They reported the discovery in Science.

The finding is notable because Barrett’s esophagus typically occurs in the lower part of the organ, close to the stomach, but now the researchers have shown that “it has so-called ‘goblet cells’ resembling a much more distant organ, the small intestine,” said lead author Lizhe Zhuang of the University of Cambridge, in a statement.

The team started by analyzing tissue samples from people with Barrett’s esophagus and from organ donors who didn’t have the condition. They made an atlas of all the cells and tissues involved in Barrett’s esophagus, and used technologies such as single-cell RNA sequencing to study how individual cells function. The analysis included tracing the genetic lineage of each cell type.

That’s how they discovered that MYC and HNF4A are key to transforming stomach cells to intestine-like cells. They discovered that esophageal adenocarcinoma cells start off as stomach cells, then change into Barrett’s and finally into cancer cells.

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The role of MYC in cancer is well known, but disrupting the gene’s ability to drive the disease has proven challenging. Its unstructured shape makes it difficult to target with drugs.

Earlier this year, scientists at Vanderbilt described a method they developed for genetically modifying MYC so it cannot interact with another protein it needs to touch off cancer, HCF1. That team had previously shown that MYC also needs the help of a protein named WDR5. Now some oncology drug developers are investigating WDR5 inhibitors, including Bristol Myers Squibb-owned Celgene.

For the University of Cambridge researchers, the main advantage of understanding the early steps in the development of Barrett’s esophagus is that it could improve the diagnosis of cancer. The researchers suggested that routinely screening patients for Barrett’s esophagus could lead to early detection and better control of esophageal cancer.