The identification and early detection of events driving the metastasis of primary tumors may help identify therapeutic targets and patients that respond to specific therapeutics. Now, an epigenetic study focused on the spread of colorectal cancer to the liver reports DNA methylation as the spark driving metastatic events.
Roadworthy researchers led by Euan J. Rodger, Rachel V. Purcell, and Aniruddha Chatterjee (University of Otago, Christchurch, New Zealand) knew that epigenetic changes occur during colorectal cancer metastasis and correlate with poor patient survival. Colorectal cancer suffers from high morbidity/mortality worldwide, with more than 1.4 million individuals developing and 0.6 million succumbing to this disease yearly. Therefore, this tyre-less team analyzed DNA methylation and gene expression in paired primary colorectal cancer cancers and liver metastases to evaluate an epigenetic link.
Let’s hear from Rodger and Colleagues on this epigenetic journey toward new therapies and better patient management:
- Reduced representation bisulfite sequencing reveals a conserved increase in DNA methylation in colorectal cancers and matched liver metastases compared to normal tissues
- Locus-specific methylation analysis identifies 244 differentially methylated CpGs (DMCs) in liver metastases compared to colorectal cancer, with most DMCs metastasis-specific or further altered in metastasis
- Overall, normal colon tissue, colorectal cancer, and liver metastases display distinct methylation patterns
- DMCs in colorectal cancer negatively correlate with chromatin accessibility
- RNA-Seq of colorectal tumors and liver metastases identify 424 genes with differential expression
- Downregulated genes participate in gene silencing mechanisms/chromatin organization and cell differentiation, while upregulated genes have functions related to extracellular matrix organization/cell adhesion and the regulation of hemostasis/response to wound healing
- Integration of 165 DMCs in genes/regulatory regions and corresponding expression levels identifies 21 potential driver-gene methylation events associated with liver metastasis (with 18 displaying negative correlations between methylation and expression)
- The genes relate to the regulation of nucleic acid processing/binding, intracellular signaling and transport, ECM/membrane and cell adhesion, and lipid/carbohydrate metabolism, with some previously linked to colorectal cancer metastasis or identified as markers for colorectal cancer diagnosis or prognosis
Overall, these findings establish DNA methylation differences as a potential factor driving the metastasis of colorectal cancer, which the authors hope will lead to a deeper understanding of this devastating disease, identify therapeutic targets, and improve patient management by matching them to appropriate treatment strategies.
Senior author Aniruddha Chatterjee states, “In Aotearoa, New Zealand, the number of people who die from colorectal cancer is particularly high. Patients with distant metastases have 5-year survival rates of only 12%. Alarmingly, the incidence of colorectal cancer is increasing in people under 50 years old and in Māori and Pasifika populations at a faster rate, and Māori and Pasifika are more likely to present directly to emergency departments with advanced colorectal tumors. Therefore, our study provides an important step towards detecting and preventing metastasis. Our future work will involve larger studies with more patients to continue this work.”
For all the details regarding this epigenetic study of colorectal cancer metastasis, see iScience, June 2023.