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Four Subtypes of Stomach Cancer Identified


Stomach cancers are a leading cause of cancer-related mortality worldwide, resulting in an estimated 723,000 deaths annually.


According to a study published online in Nature (23 July 2014), and performed by The Cancer Genome Atlas (TCGA) Network, it was observed that stomach cancers fall into four distinct molecular subtypes. According to the authors, this discovery could change how researchers think about developing treatments for stomach cancer, also called gastric cancers or gastric adenocarcinomas, and instead of considering gastric cancer as a single disease, as has been done in the past, researchers will now be able to explore therapies in defined sets of patients whose tumors have specific genomic abnormalities. Previous attempts to examine the clinical characteristics of gastric cancer were hindered by how differently cancer cells can look under a microscope, even when from the same tumor. It is hoped that the new classification system will serve as a valuable adjunct to the current pathology classification system, which has two categories: diffuse and intestinal.


The study used six molecular analysis platforms including DNA sequencing, RNA sequencing, and protein arrays to identify the new subgroups through complex statistical analyses of molecular data from 295 tumors. Tumors in the first group, which represented 9% of the tumors, were positive for Epstein-Barr virus (EBV) and had several other molecular commonalities. Tumors in a second subgroup (22% of the tumors) had high microsatellite instability (MSI), which is the tendency for mutations to accumulate in repeated sequences of DNA. 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, which comprised 20% of the tumors, were considered to have a low level of SCNAs and were called genomically stable. The remaining 50% of tumors were classified as chromosomally unstable, with a high level of SCNAs.


The EBV-positive subgroup of tumors was of particular interest. EBV is best known in the United States as the cause of infectious mononucleosis, which is characterized by fever, sore throat, and swollen lymph glands, especially in the neck. EBV is also suspected of causing certain cancers, including nasopharyngeal carcinoma and some types of lymphoma. Previous research had shown that EBV can be detected in a minority of gastric adenocarcinomas and that EBV genes are expressed in those tumors. However, this study found that the presence of EBV in gastric tumors is associated with a number of other molecular characteristics.


In the study, the authors observed that EBV-positive tumors displayed a high frequency of mutations in the PIK3CA gene, which codes for a component of a protein, PI3-kinase, which is essential for cell growth and division and many other cellular activities that are important in cancer. Although 80% of EBV-positive tumors harbored a protein-changing alteration in PIK3CA, PIK3CA mutations were found in 3% to 42% of tumors of the other gastric cancer subtypes. The authors suggested that EBV-positive tumors might respond to PI3-kinase inhibitors, some of which are in the early stages of testing in clinical trials but are not yet approved by the US FDA for general use.


Some tumors in the EBV-positive subgroup also showed more gene copies being produced in a chromosomal region that contains the JAK2 gene. The JAK2 protein facilitates cell growth and division, and the increased expression of JAK2 may inappropriately activate cell growth. The amplified region also contains the genes for two proteins, PD-L1 and PD-L2, which suppress immune responses; their increased expression may help tumors escape destruction by the immune system. The authors suggested that these findings support the evaluation of JAK2 inhibitors and PD-L1/2 antagonists for the treatment of EBV-positive gastric cancers.


Finally, the EBV-positive subgroup showed a far higher prevalence of DNA hypermethylation than any other reported cancer subtype. Methylation is the process of adding methyl groups to DNA, which reduces gene expression. Hypermethylation occurs when this mechanism continues aberrantly, quieting genes that should be active. In the EBV-positive tumor subgroup, hypermethylation was most often observed in the promoter regions of genes, which would prevent the expression of the genes.


Important insights also came from analyses of the three other gastric cancer subgroups. For example, tumors of the genomically stable subtype contained frequent mutations in a gene called RHOA, whose product interacts with other cellular proteins to help cells change shape and migrate, which may be important in tumor growth. This finding suggests possible targets for treating tumors of this subtype. And tumors of the chromosomal unstable subtype contained frequent amplifications of genes that encode receptor proteins on the outside of the cell, leading to the promotion of aberrant cell growth. Drugs are already available to curb the activity of some of these proteins.


TCGA is jointly managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health (NIH), to comprehensively characterize the genomes of more than 30 types of cancer.


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