Genomic analysis clarifies subtypes of gastric cancer

In a massive effort to catalog the molecular causes of stomach cancer, scientists have identified four subtypes of tumors based on shared mutations and other molecular abnormalities. They say the new classification promises to advance clinical research to develop improved therapies for the third-leading cancer killer worldwide.

In a report in Nature (2014; doi:10.1038/nature13480), investigators of The Cancer Genome Atlas Research Network said they analyzed 295 samples of gastric cancer, looking for ways to sort them into groups with similar key DNA defects and molecular aberrations. It was extremely important, they said, to identify categories that would be useful in guiding therapy for patients.

"We clearly converged on four groups of gastric cancer with distinct features and classes of molecular alterations," said corresponding author Adam Bass, MD. He is director for translational research for the Center for Esophageal and Gastric Cancer at Dana-Farber, and an associate member of the Broad Institute of MIT and Harvard, located in Boston, Massachusetts.

Grouping the cancers in this way will help researchers enroll patients in clinical trials that test drugs designed to target their particular stomach cancer subtype, said Bass. There is an urgent need for new therapies because these cancers are aggressive and the 5-year survival rate is 20% to 25%.

Gastric adenocarcinomas, which comprise the vast majority of stomach cancers, cause more than 700,000 deaths worldwide each year. Research on the biology of stomach cancer and the development of new therapies has been difficult because of its diversity and the presence of different pathologic forms.

When computational methods were applied to the large amount of data from the genomic analyses in this study, the cancers fell into four subtypes. The first subtype was tumors containing the Epstein-Barr virus (EBV), along with mutations in the PIK3CA gene pathway, extreme DNA hypermethylation, and extra copies of PD-L1 and PD-L2 genes. This group made up approximately 10% of the cancers.

The second subtype was tumors in which malfunctioning DNA repair mechanisms cause a high rate of mutations—many of them leading to potential activation of cancer-related signaling proteins that can be targeted with novel precision drugs. About 20% of tumors fell into this subtype.

The largest category of tumors, making up about half of the cancer specimens, was termed chromosomally unstable. These cancer cells contained a jumble of extra or missing pieces of genes and chromosomes. Bass said these tumors "have a striking number of genomic amplifications [extra copies] of key cancer-promoting genes" for which targeted therapies exist or are in development. This subtype of tumor is frequently found in the junction between the stomach and the esophagus—a type of stomach cancer that has been dramatically increasing in the United States, he said.

The fourth group of tumors was termed genomically stable as they lacked the molecular features of the other three types. These tumors, making up 20% of the specimens were largely those of a specific class of gastric cancer called diffuse-type tumors.

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