Study Defines Four Molecular Subtypes of Gastric Cancer


Key Points

  • A new molecular classification system divides gastric cancer into four major genomic subtypes: EBV-infected tumors, microsatellite unstable tumors, genomically stable tumors,and chromosomally unstable tumors.
  • The molecular subtypes show distinct salient genomic features, which should help identify specific populations of patients who should be evaluated in clinical trials and who may be candidates for targeted therapy.
  • The classification system may help improve the survival rates of gastric cancer.

Investigators of The Cancer Genome Atlas project have developed a molecular classification that divides gastric cancer into four major genomic subtypes, according to a study published in Nature. They include (1) tumors positive for the Epstein-Barr virus (EBV) that display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCDILG2 (also known as PD-L2); (2) microsatellite unstable tumors that show elevated rates, including mutations of genes encoding targetable oncogenic signaling proteins; (3) genomically stable tumors that are enriched for the diffuse histologic variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and (4) tumors with chromosomal instability that show marked aneuploidy and focal amplification of receptor tyrosine kinases. The classification system may hasten the development of targeted therapies to improve survival.

Study Methodology

The researchers collected fresh, frozen tissue specimens and blood samples from 295 patients with gastric adenocarcinomas from hospitals around the world who had not been treated with chemotherapy or radiation. The tissue samples were analyzed using six molecular analysis technologies, including sequencing the protein-coding DNA in each tumor, detecting mutations or missing or extra copies of gene sequences, determining the methylation status of DNA, sequencing the messenger RNA and microRNA in the tumors, and assessing expression of key proteins.


Their analysis led to the division of gastric cancer into the four subtypes. Tumors containing EBV made up about 10% of the cancers, microsatellite unstable tumors made up about 20%, the chromosomally unstable tumors made up about half of the cancer specimens, and genomically stable tumors made up about 20% of the specimens.

Sorting the tumors into groups with similar key DNA defects and molecular aberrations will identify specific populations of patients with gastric cancer who should be evaluated in clinical trials and may help guide targeted therapies, according to the researchers.

“[Gastric cancer] is a very heterogeneous disease, but most clinical trials have taken a one-size fits all approach and attempted to find a single optimal therapy to apply across gastric cancers,” said Adam Bass, MD, a coauthor of the study and Director for Translational Research for the Center for Esophageal and Gastric Cancer at Dana-Farber Cancer Institute, and Associate Member of the Broad Institute of MIT and Harvard, in a statement.

According to GLOBOCAN, worldwide, gastric adenocarcinomas cause more than 700,000 deaths each year. The American Cancer Society estimates that 22,200 cases of gastric cancer will be diagnosed in the United States in 2014, and about nearly 11,000 people will die from the cancer.

Funding for this study was provided by the Intramural Research Program and the National Institutes of Health. The study authors reported no conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.