4 December 2020

Tumor microenvironment could play an important role in gallbladder carcinogenesis

A new study from the Andersen Group, BRIC at University of Copenhagen and researchers at the Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, part of the National Institutes of Health in the US, suggests that the tumor microenvironment and immune profiles could play important roles in gallbladder carcinogenesis and progression. The finding warrants evaluation in future clinical studies alongside genomic profiling.

“Though most cancers are traditionally viewed as mutation-driven diseases, non-genetic alterations in tumor cells and cells in the microenvironment, including immune cells are pervasive in the initiation and progression of cancer. These dynamic aspects of disease behavior are poorly characterized in GBC,” according to first-authors Drs. Chirag Nepal, Bin Zhu and Colm J O’Rourke.

In a new study, researchers from the Andersen group at BRIC and DCEG in the US investigated molecular characteristics of gallbladder cancer (GBC) in 190 GBC patients. GBC is a rare and highly aggressive cancer, and to date, the molecular understanding of this cancer type is limited.

Survival subtypes are more closely related to differences in the tumor microenvironment than mutation burden in gallbladder tumor tissue

The researchers defined a signature of 95-genes that stratified patients into three molecular subtypes associated with survival. Overall, survival outcomes presented genomic alterations more highly related to differences in the tumor microenvironment than mutation burden or copy number alterations.

Thus, GBC tumors with good survival were more likely to have a healthy microenvironment, characterized by increased metabolism, and evidence of functional T cells infiltrating the tumor mass. These findings suggest that immune checkpoint inhibitors may be useful in this patient subset. In contrast, molecular subtypes associated with poor survival were related to immunosuppressive microenvironments, accumulation of immunosuppressive cells, and T cell dysfunction, suggesting that either inhibitors of the MAPK or TGF-β signaling pathways may be more effective in this patient subset. The researchers also identified a novel fusion gene (TPPP:BRD9) associated with good survival.

“GBC pathobiology is particularly important because, given its status as a rare disease, screening of the general population is not likely to be feasible even if adequate biomarkers are identified. Without valid biomarkers, GBC will continue to be diagnosed at late stage,” says Associate Professor Jesper B Andersen, group leader.

The causes of GBC remain unclear. However, in this study the researchers found evidence of aflatoxin exposure in a subset of the tumors. Aflatoxins are a family of toxins produced by certain fungi that grow on agricultural crops such as corn and peanuts.

“About 40% (39/92) of the cases we evaluated had the aflatoxin signature, and these mutations tended to be present in the majority of the cancer cells, suggesting that aflatoxin had an effect early in the development of cancer,” says Jill Koshiol, principal investigator at DCEG.


In the study, the researchers profiled the mutational landscapes of GBC tumors to investigate molecular correlates associated to GBC survival and in a subset of tumors, integrated matched transcriptome, DNA methylation and copy number alteration data to explore GBC prognostic subtypes based on their molecular profiles. The study constitutes the largest integrated omics landscape of GBC tumors. A critical next step is to determine if the survival-associated molecular subtypes identified in this study can be replicated in another set of gallbladder cancers. If so, then it will be important to identify the etiologic factors associated with these subtypes.


Integrative molecular characterization of gallbladder cancer reveals microenvironment-associated subtypes