Study IDs esophageal cancer's molecular signature

A probe of the DNA of esophageal adenocarcinomas (EACs) reveals that many share a distinctive mix-up of letters of the genetic code and more than 20 mutated genes that had not previously been linked to the disease, according to a new study in Nature Genetics (March 24, 2013).

The research, led by scientists at Dana-Farber Cancer Institute, the Broad Institute, and other research centers, may offer clues to why EAC rates have risen so sharply. The findings point to an array of abnormal genes and proteins that may be lynchpins of EAC cell growth and, therefore, serve as targets for new therapies, the researchers said.

Esophageal adenocarcinomas, particularly those at the gastroesophageal junction, were extremely uncommon 40 years ago but now account for approximately 15,000 new cases in the U.S. annually, the study authors noted in a press release. The disease generally has a poor prognosis: Five years after diagnosis, only about 15% of patients are still alive.

The study's goal was to identify abnormalities within the genome of EAC cells to better understand the tumors, diagnose them earlier, and develop better treatments, the researchers said.

For this study, they sequenced specific sections of DNA in cells from 149 EAC tissue samples, reading the individual letters of the genetic code within those areas. They focused on the 1% of the genome that holds the codes for making cell proteins. They also sequenced the entire genome -- all the DNA within the cell nucleus -- of cells from 15 of these samples. Prior to this study, the largest sequencing study of EAC involved only a dozen tumor samples.

The researchers found a pattern of DNA changes that had not been seen before in any other cancers. The pattern involved a subtle swap in one of the four "nucleobases" that form the rungs of the DNA double helix, often designated by the letters C, T, G, and A. The investigators found that in many places where an A nucleobase was followed by another A nucleobase, the second A was replaced by a C, a process known as transversion.

Overall, about one-third of all the mutations the researchers discovered within these cells involved this type of transversion. In some tumor samples, these transversions accounted for nearly half of all mutations, the study authors reported.

They also identified 26 genes that were frequently mutated in the tumor samples. Five of these were classic cancer genes that had previously been implicated in EAC, and the others were involved in various cell processes.