TCGA Identifies Four Gastric Cancer Subtypes

A new analysis identified four genomic subtypes for gastric cancer.

Gastric cancer is among the leading causes of cancer deaths around the world, but lags behind other malignancies in our understanding of genomic drivers and targeted agents. A new study, though, has aimed to improve that situation, proposing a new classification of gastric cancers into four genomic subtypes that could eventually yield better treatment paradigms.

Existing classification schemes for gastric cancer divides them by adenocarcinoma and subdivides into intestinal and diffuse types, or into papillary, tubular, mucinous, and poorly cohesive subtypes. “These classification systems have little clinical utility, making the development of robust classifiers that can guide patient therapy an urgent priority,” wrote researchers for The Cancer Genome Atlas Research Network led by Adam Bass, MD, of Dana-Farber Cancer Institute in Boston.

The researchers obtained frozen samples of gastric adenocarcinoma from 295 patients who had not been treated with prior chemotherapy or radiotherapy. They conducted a variety of genomic analyses, including whole genome sequencing on 107 tumor/germline pairs. The results of this analysis were published online ahead of print on July 23 in Nature.

They found that gastric adenocarcinomas can be divided into four distinct groups: tumors that are positive for Epstein-Barr virus; microsatellite unstable tumors; genomically stable tumors; and tumors with chromosomal instability.

The first category, those tumors positive for Epstein-Barr virus, had several genomic signatures. They tended to display recurrent PIK3CA mutations, as well as extreme DNA hypermethylation, and amplification of the genes JAK2, PD-L1, and PD-L2; these accounted for 9% of the samples. The microsatellite unstable tumors showed elevated mutation rates especially of oncogenic signaling proteins already considered targetable, and made up 22% of the cohort.

The genomically stable tumors, making up 20% of the total, were enriched for the diffuse histological variant of adenocarcinoma and had mutations of the RHOA gene. Finally, 50% of the samples were considered chromosomally unstable; these showed significant aneuploidy along with focal amplification of receptor tyrosine kinases.

“A key advance with this project is that we have identified and developed a much more useful classification system to find groups of gastric cancer that have distinct molecular features, and at the same time, we also identified key targets to pursue in different groups of patients,” Bass said in a press release. “This will provide a strong foundation for categorizing the disease and for doing so in a way in which we can develop clinical trials based on some of the critical molecular alterations that are driving different classes of cancers.”