Four Subtypes of Gastric Cancer Identified

Gastric adenocarcinoma, which comprises the majority of stomach cancers, is often treated as a single disease, but it is actually multifaceted. Investigators from The Cancer Genome Atlas (TCGA) have uncovered 4 subtypes, each with distinct molecular aberrations (Nature 2014 July 23 [Epub ahead of print]).

The researchers performed 6 types of molecular characterization, including DNA methylation profiling, Epstein-Barr virus (EBV) status, whole-exome sequencing, and somatic copy-number analysis on gastric adenocarcinoma tissue from 295 untreated patients. Samples were also examined for microsatellite instability (MSI).

“We wanted to develop a robust classification system for gastric adenocarcinoma that's feasible in the real world,” says corresponding author Adam Bass, MD, director of Dana-Farber Cancer Institute's Center for Esophageal and Gastric Cancer in Boston, MA. “So we determined reasonable markers for clustering these tumors.”

About 10% of the tumors were EBV-positive, with extensive DNA hypermethylation. Of this group, 80% harbored PIK3CA mutations, versus 3% to 42% for the remaining subtypes. Elevated PD-L1 and PD-L2 levels were also observed.

“The data from this group were intriguing,” says Bass. “Immune evasion could be a salient feature of EBV-positive gastric cancers.”

Ronan Kelly, MD, MBA, director of the Johns Hopkins Gastroesophageal Cancer Therapeutics program in Baltimore, MD, agrees, adding that immunotherapies are worth investigating. “We've reached a plateau with chemotherapy,” he says. “My colleagues at Johns Hopkins and I have data indicating that a significant number of these patients may benefit from PD-1/PD-L1 inhibitors.” He hopes to test this hypothesis in a clinical trial.

A second subtype, comprising 20% of tumors, displayed high MSI associated with mutations in KRAS, ERBB3, and PTEN. “In colon cancer, tumors with MSI respond differently to adjuvant chemotherapy, which is factored into the [treatment] decision process,” notes Bass. “We haven't done the same for gastric cancer, but this could change.”

Fully half of the tumors made up a third subtype, featuring chromosomal instability (CIN) and amplification of key genes, including EGFR. These were more prevalent in the gastroesophageal junction (GEJ), and notably—given the activity of ramucirumab (Cyramza; Lilly Oncology) in GEJ adenocarcinoma—VEGFA was also recurrently amplified. It would be interesting, Kelly says, to retrospectively analyze data from the REGARD and RAINBOW trials, to see if patients who benefited from ramucirumab had CIN tumors, because “we still don't have a biomarker for VEGF therapies.”

Finally, the researchers characterized a fourth group lacking extensive copy-number alterations, mainly diffuse-type gastric tumors, as “genomically stable.” They found RHOA mutations almost exclusively in this subtype, and hypothesized that dysfunctional RHOA signaling contributes to a hallmark of diffuse tumors: diminished cellular cohesion. It potentially opens new therapeutic avenues for this deadly type of gastric cancer, says Bass.

“It's too early to know if what we've found will have similar impact as the discovery of different breast cancer subtypes,” he adds, “but I think this is a more rational way of categorizing gastric cancer patients.”

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