A disease as versatile as it is resilient, cancer is difficult to treat and may return even after successful therapy. Although certain gene mutations are known to be associated with cancer development, progression and relapse, the contributing effect of gene promoters—DNA sequences involved in the regulation of gene expression—remains obscure.
To better understand the role of gene promoters in cancer, researchers led by Jonathan Göke and Patrick Tan at the Genome Institute of Singapore (GIS), analyzed data from 18,468 patient-derived tissue samples representing 42 different cancer types.
“Cancer patients often differ from one another genetically, but what we wanted to find out was whether the gene promoters of these patients also show variation,” said Göke.
The researchers inferred promoter sequences from publicly available RNA sequencing data, categorizing them as major promoters, minor promoters and inactive promoters based on the total amount of gene expression initiated at each promoter. Major promoters were the most active in initiating gene expression.
“Next, we selected genes which could be expressed from multiple promoters and tested whether the top ten percent of patients with the highest promoter activity would show differences in survival compared to the rest of the patients,” he said.
The team found that the use of alternative promoters—DNA sequences that regulate the same gene but in different contexts, such as in different organs—was associated with lower patient survival. For example, examining the gene ERBB2 which is known to be expressed in aggressive tumor types, the researchers observed that brain cancer patients with high activity at alternative promoters had poorer clinical outcomes.
Further experiments also showed that alternative promoters were responsible for producing different blueprints for protein synthesis, which could drastically alter protein function.
“If an alternative promoter affects an oncogene or a tumor suppressor protein, this could directly influence cancer biology,” Göke explained. “Our findings highlight these possibilities and suggest that promoters possibly contribute to many aspects of cancer.”
The team plans to follow up on these findings by examining whether alternative promoters directly influence tumor growth in cancer cell lines. “We are also working on new, third-generation transcriptomics technology that might help to better quantify promoters from RNA sequencing data,” Göke said.
The A*STAR-affiliated researcher contributing to this research is from the Genome Institute of Singapore (GIS).
