The researchers, who report their findings in the journal Nature, are members of The Cancer Genome Atlas (TCGA), a group of scientists in the US that formed in 2005 and is characterizing the genomes of more than 30 types of cancer.
Stomach cancer is a leading cause of cancer-related deaths worldwide – estimates suggest around 723,000 people die of the disease every year. In the US, the American Cancer Society estimate that in 2014, about 22,220 people will be diagnosed with the disease, and about 10,990 will die of it.
New system based on molecular features instead of cell and tissue characteristics
The current system for classifying stomach cancer puts it into two groups: diffuse and intestinal. The system uses mainly changes in cell and tissue to distinguish them. The researchers note that it is not easy to classify gastric cancer using this system because cancer cells can look quite different under the microscope, even when they are from the same tumor.
Adam Bass, assistant professor in the Department of Medicine at Harvard Medical School, Boston, MA, was one of the lead investigators on the study. He explains the advantage of the new classification system:
“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.”
“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,” he adds.
In the study, Prof. Bass and colleagues carried out complex statistical analyses of molecular features from 295 tumors. The analyses used six types of genetic data, including DNA sequencing, RNA sequencing and protein arrays.
Four subgroups of stomach cancer
They concluded there are four subgroups of stomach cancer:
- Type 1, representing 9% of the tumors they analyzed, were positive for Epstein-Barr virus (EBV) and had several other molecular features in common.
- Type 2 (22% of tumors) showed high level of “microsatellite instability” or MSI, where mutations tend to accumulate in repeated sequences of DNA.
- Type 3 (20%) were classed as genomically stable because they showed a low level of somatic copy number alterations (SCNAs) – which can result from duplication or deletion of sections of the genome.
- Type 4 (50% of tumors) were classed as chromosomally unstable, because they showed a high level of SCNAs.
The researchers were particularly interested in the group that was positive for EBV, which in the US is best known as the cause of infectious mononucleosis or glandular fever. EBV is also believed to cause some cancers, including nasopharyngeal carcinoma, a type of head and neck cancer, and some types of lymphoma.
EBV has been found in a small minority of stomach cancers that also express EBV genes in their tumors. But this study also links EBV in gastric tumors to other molecular features.
For example, one of the molecular features they found in EBV-positive tumors was a tendency for higher rates of PIK3CA gene mutations. This gene codes for a protein called PI3-kinase that is important for cell growth and division, and other cell functions relevant to cancer.
Such a discovery might indicate that stomach cancers positive for EBV might respond to PI3-kinase inhibitors, says the team. These drugs are currently in the early stages of clinical trials in the US.
The team also made interesting discoveries in the other three subgroups. For example, tumors of the genomically stable subtype showed frequent mutations in the gene RHOA, whose protein interacts with other cell proteins to help cells change shape and migrate – this can be an important feature in tumor growth.
Also, chromosomally unstable tumor types showed frequent amplifications of genes that code for receptor proteins that are linked to abnormal cell growth. Drugs are already in use that might curb their activity, says the team.
TCGA is jointly managed by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI), both within the National Institutes of Health (NIH).