Researchers Characterize 4 Molecular Subtypes of Gastric Cancer

Stomach cancers fall into 4 distinct molecular subtypes, researchers report. This information could lead to new strategies to treat patients with specific types of gastric cancer.

In the study, published online July 23, 2014, in Nature, researchers with The Cancer Genome Atlas Network (TCGA) report findings that could change how researchers think about developing drugs for and treating patients with gastric adenocarcinomas.

Drug Discovery and Development wrote that tumors in the first group (9% of the tumors) were positive for Epstein-Barr virus (EBV) and contained recurrent mutations in PIK3CA, high levels of DNA hypermethylation, and amplification of JAK2, CD274 (also known as PDL1), and PDCD1LG2 (also known as PDL2).

Tumors in a second subgroup (22% of the tumors) had high levels of microsatellite instability (MSI)—a tendency for mutations to accumulate in repeated sequences of DNA, including mutations of genes encoding oncogenic signaling proteins.

The remaining subgroups differed in the level of somatic copy number alterations (SCNAs), which can result from duplication or deletion of sections of the genome. The tumors in the third subgroup (20% of the tumors) were considered to have a low level of SCNAs and were called genomically stable. These contained many variants and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins

The remaining 50% of tumors were characterized by chromosomal instability, with high levels of aneuploidy and amplifications of genes encoding receptor tyrosine kinases.

A press release from the NIH said that researchers can now explore therapies in defined sets of patients whose tumors have specific genomic abnormalities. Scientists hope that the new classification system will serve as a valuable adjunct to the current pathology classification system, which has 2 categories: diffuse and intestinal.

“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,” said Bass (Dana-Farber Cancer Institute). “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.”

The NIH press release says that the EBV-positive subgroup of tumors was of particular interest. EBV causes infectious mononucleosis, but is also suspected of causing certain cancers. EBV has been detected in a small percentage of gastric adenocarcinomas, and EBV genes are expressed in those tumors. However, Bass et al. associated the presence of EBV in gastric tumors with a number of other molecular characteristics.

The press release explains that although 80% of the EBV-positive tumors contained protein-changing alteration in PIK3CA, PIK3CA mutations were also found in 3%–42% of tumors of the other subtypes. Bass et al. propose that EBV-positive tumors might respond to PI3 kinase inhibitors, some of which are in early-stage clinical trials.

Some tumors in the EBV-positive subgroup also had extra copies of the gene JAK2. The amplified region also contains the genes encoding PDL1 and PDL2, which regulate immune responses. Increased levels of these proteins could help tumors escape immune detection or destruction. These findings support the evaluation of JAK2 inhibitors and PDL1 and PDL2 antagonists for the treatment of EBV-positive gastric cancers.

“This study reinforces the value of the approach we are using to study genomic diversity and similarity among tumors of many different cancer types,” said NCI Director Harold Varmus. “Only such a systematic analysis could have yielded observations about the association between EBV and several provocative molecular characteristics.”

Important insights also came from analyses of the 3 other gastric cancer subgroups. For example, tumors of the genomically stable subtype contained frequent mutations in RHOA, whose product interacts with other proteins to help cells change shape and migrate—important features of tumor progression.

Tumors of the chromosomal unstable subtype contained frequent amplifications of genes that encode extracellular receptor proteins. Drugs are already available to reduce the activity of some of these proteins.

TCGA-generated data are freely available at the TCGA Data Portal.

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