Scientists have uncovered a new class of master control elements in stomach cancer called “super-enhancers”, which control critical cancer genes and proteins required for stomach tumours to survive and grow.
The team’s generation of this unprecedented and comprehensive catalogue of stomach cancer super-enhancers is an important milestone for the community. Currently, stomach cancer is the fifth most common cancer worldwide and the third leading cause of global cancer death . Most gastric cancers are diagnosed late, and the disease is often resistant to current clinical treatments.
By studying super-enhancers in stomach tumours, the team was able to shed light on how these elements impact the risk of stomach cancer development and progression of the disease. For example, stomach cancer patients whose tumours exhibited high numbers of super-enhancers exhibited a significantly poorer survival rate. Selective activation of these super-enhancers could explain why certain groups of people are at risk of developing the disease.
These tissue-specific super-enhancers also represent a previously untapped reservoir of cancer vulnerability, acting to bridge oncogenic signalling to tissue-specific features of malignancy. Thus, studying the mechanisms driving the development of super-enhancers in stomach cancer may lead to novel therapies. Specifically, the team also identified two DNA-binding proteins as drivers for the formation of tumour-specific super-enhancers. These may serve as potential drug targets for stomach cancer.
The researchers were able to make this finding using a highly sensitive, “made-in-Singapore” technology, called Nano-ChIPseq. Developed at A*STAR’s Genome Institute of Singapore (GIS), Nano-ChIPseq enables the study of epigenomic changes in clinical samples obtained directly from stomach cancer patients, rather than laboratory cultured cell lines. Unlike DNA which is stable and unchanging, epigenomic instructions are strongly influenced by factors such as food, infectious agents, and chemicals, suggesting that they can be modified by environmental risk factors.
“Future work in our lab will investigate how such super-enhancers can be disrupted by drugs, which will open up new avenues for cancer therapy,” said the study’s corresponding author Prof Patrick Tan, Deputy Executive Director of A*STAR’s Biomedical Research Council and an associate faculty member at the GIS. “We hope that our findings will encourage the scientific community to embrace our technology as a means to rapidly uncover master control elements that are highly relevant to diseases and clinical outcomes. This effort may eventually change the way stomach and other cancers are managed, which will enhance the clinical outcomes of cancer patients.”
Published in scientific journal Nature Communications, this study was led by GIS, in collaboration with Duke-NUS Medical School, Cancer Science Institute of Singapore at the National University of Singapore (NUS), Singapore General Hospital (SGH), Weatherall Institute of Molecular Medicine at Oxford University, and the Singapore Gastric Cancer Consortium (SGCC). Commercialisation of the Nano-ChIPseq platform is currently supported through gap funding awarded by ETPL Pte Ltd, the commercialisation arm of A*STAR.
“I felt something awesome will be coming when I heard about the new method, Nano-ChIPseq. The study suggests that extensive alterations in gene regulation, and not genes themselves, explain deep mysteries of gastric cancer, which are known to exhibit small numbers of mutations and deep involvement of bacterial infection, an environmental factor. Naturally, development of novel therapeutic strategies must take account of these findings,” said Dr Toshikazu Ushijima, Chief of Division of Epigenomics at the National Cancer Center Research Institute in Japan, and a member of the SGCC Scientific Advisory Board.
GIS Executive Director Prof Ng Huck Hui added, “This is a remarkable technological breakthrough for the community. As we constantly work to find better treatments for cancer, it is also important that we find more efficient ways to study how epigenomic changes can drive the formation of cancerous cells from healthy cells. A greater understanding about molecular changes in diseases can potentially lead to early therapeutic intervention and improved care for the patients.”