Gastric cancer has a claudin-low molecular subtype

Last Updated: 2017-06-30

By Reuters Staff

NEW YORK (Reuters Health) - In keeping with breast and bladder cancers, gastric cancer also has a molecular subtype characterized by low expression of claudins, according to North Carolina-based researchers.

Such tumors, which lack luminal differentiation marker expression, “are associated with poor prognosis compared with luminal tumors,” Dr. Benjamin G. Vincent and colleagues at the University of North Carolina at Chapel Hill note in JCO Precision Oncology, online June 19.

Among their characteristics are low expression of tight-junction claudins, enrichment for epithelial-to-mesenchymal transition (EMT) markers and tumor-initiating cell (TIC) features.

To investigate the possible occurrence of a claudin-low subtype in gastric cancer, the researchers used gene signatures with biologic characteristics known to define the claudin-low subtype in breast and bladder cancers.

They assessed 415 tumors from The Cancer Genome Atlas (TCGA) gastric cancer mRNA data set for these signatures, and validated the results in 300 samples from the Asian Cancer Research Group (ACRG) data set.

The team identified 46 gastric tumors with consensus enrichment for claudin-low features. They were most commonly of the diffuse histologic type (82%), and 78% had originally been classified as the TCGA genomically stable (GS) subtype.

In the ACRG data set, 28 claudin-low tumors were identified and were phenotypically similar to those found in the TCGA data set.

Compared with the non-claudin-low GS subtype, the claudin-low variant had significant activation in the Rho family of GTPases signaling. This, say the researchers, "appears to play a key role in its EMT and TIC properties."

Overall survival was also significantly worse for claudin-low tumors. After adjustment, compared with the GS subtype, the hazard ratio was 2.1 in the TCGA cohort and 2.32 in the ACRG cohort.

This poor prognosis, the researchers suggest, is "likely related to therapeutic resistance as a result of its EMT and TIC phenotypes."

They further note that a Rho-associated protein kinase inhibitor, fasudil, has shown success in reversing such chemoresistance and that it works synergistically with cisplatin chemotherapy in xenograft models.

Thus, they conclude, "future studies that explore the combination of fasudil and chemotherapy for treatment of gastric claudin-low tumors will be of great interest."

Dr. Vincent did not respond to requests for comments.

SOURCE: http://bit.ly/2sthnvy

JCO Precis Oncol 2017.