New research in colorectal cancers directed by investigators at the Johns Hopkins Kimmel Cancer Center suggests that expression of transcription factors — proteins that help turn specific genes on or off by binding to nearby DNA — may play a central role in the degree of DNA methylation across the genome, contributing to the development of different subtypes of these cancers. Methylation is a process in which certain chemical groups attach to areas of DNA that guide genes’ on/off switches.
Studying the expression of these transcription factors in patients with colorectal cancers could reveal biomarkers to help determine overall survival in people with a subgroup of colorectal cancers who generally have better survival rates and, importantly, respond better to immune checkpoint therapy — a type of immunotherapy that releases restraints that cancer cells place on the immune response — and other treatments. Similar patterns of transcription factor expression could be seen by the researchers even in precancerous polyps, and could potentially be used by physicians to determine which patients need closer follow-up to prevent cancer development.
A description of the work was published online July 24 in the journal Proceedings of the National Academy of Sciences.
In a series of laboratory studies of genetic material taken from tubular adenomas (precancerous polyps in the colon) and colon tumors, the researchers linked cancer-specific transcription factor expression alterations to methylation alterations in colorectal cancers and their premalignant precursor lesions, which provided insights into the origins and evolution of different molecular subtypes of colorectal cancers.
Specifically, researchers observed that some regions of the genome undergoing increased methylation tend to have binding sites for transcription factors that are downregulated, or have low expression. In some types of colon cancer, based on the types of genetic alterations associated with the cancer, transcription factors are upregulated or have higher expression.
The findings suggest that cancer-specific methylation differences potentially evolve due to perturbation in the activity or expression of transcription factors. Similar changes in DNA methylation patterns were observed in precancerous polyps.
