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Sequencing Studies Follow Progression from Barrett's Esophagus to Esophageal Cancer

NEW YORK (GenomeWeb) – A pair of studies published online today in Nature Genetics by teams in the US and UK outlined mutational and clonal architecture patterns associated with progression from Barrett's esophagus to esophageal cancer.

The papers mark the latest in a series of studies aimed at understanding cancer emergence in a subset of individuals with Barrett's esophagus, a benign condition associated with gastric reflux disease in which cells in the lower esophagus begin to resemble those in the intestine.

For one of these studies, researchers at the Broad Institute, the Dana-Farber Cancer Institute, Massachusetts General Hospital, and elsewhere did exome sequencing on matched Barrett's esophagus, esophageal adenocarcinoma, and normal samples from 25 individuals who developed esophageal cancer.

They also used exome sequencing to track relationships between the various mutational sub-clones present in sequential samples from five individuals who developed esophageal cancer from Barrett's esophagus.

Together, these data revealed rampant mutations in the well-known cancer gene TP53, even in Barrett's esophagus samples representing early-stage disease. In contrast, the team saw a rise in structural variants, including cancer-promoting gene amplifications, relatively late in cancer progression — findings the group verified by re-analyzing existing exome sequence data for 144 esophageal adenocarcinoma tumors.

In well over half the cases, such oncogene amplification was part of a genome doubling process that marked the march towards cancer development. That appeared to contribute to dramatic clonal differences between tumors and corresponding Barrett's esophagus samples in 11 of the 25 individuals tested.

"These data suggest that many [esophageal adenocarcinomas] emerge not through the gradual accumulation of tumor-suppressor alterations but rather through a more direct path whereby a TP53-mutant cell undergoes doubling, followed by the acquisition of oncogenic amplifications," authors of the study explained.

Members of the Esophageal Cancer Clinical and Molecular Stratification Consortium, or OCCAMS, saw a similar rise in copy number alterations during esophageal cancer development when they did whole-genome sequencing on matched Barrett's esophagus, esophageal adenocarcinoma, and normal samples from 23 individuals.

That group also detected high rates of mutation in Barrett's esophagus samples, including those that had not reached an advanced, dysplastic stage. And results from that analysis indicated that both esophageal adenocarcinoma and the Barrett's esophagus samples frequently carry mutational signatures that seem to stem from exposure to stomach acid.

The OCCAMS researchers described similar mutational signatures in an esophageal adenocarcinoma paper appearing in Nature Genetics last year. That work also pointed to the presence of apparent driver gene mutations in individuals with esophageal cancer as well as some individuals with seemingly stable Barrett's esophagus disease.

As in their previous paper, the OCCAMS members relied on a so-called Cytosponge device to sample cells from the esophagus without an endoscope. In a 58-year-old man who was tested 73 times over three years, for example, the Cytosponge sample provided a peek at five sub-clones from the Barrett's esophagus stage of disease that expanded, remained steady, or were replaced later in the disease process.

"Barrett's esophagus and the cancer share many mutations, but we are now a step closer to understanding which are the important mutations that tip the condition over into a potentially deadly form of cancer," co-first author Caryn Ross-Innes, with the University of Cambridge, said in a statement.

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