Epigenetic differences in the tumor suppressor genes MLH1 and p16INK4a between Nepalese and Swedish patients with colorectal cancer

Colorectal cancer (CRC) is one of the most prevalent cancer types worldwide, exhibiting significant variance in incidence rates across different ethnicities and geographical regions. Notably, there is a rising incidence of CRC among younger adults, particularly evident in advanced stages, with a more pronounced trend observed in developing nations. Epigenetic alterations potentially play a role in the early onset of CRC and could elucidate interpopulation disparities. This study aimed to examine DNA methylation levels in the tumor suppressor genes and , comparing Nepalese and Swedish patients with CRC. Patients who underwent CRC surgery at Tribhuvan University Teaching Hospital, Nepal (n=39), and Sahlgrenska University Hospital, Sweden (n=39) were included. Demographic and clinicopathological data were analyzed, and pyrosequencing was employed to determine methylation levels in the promoter region and the first exon of in tumor tissues and adjacent mucosa located 10 cm from the tumor site. Subsequently, methylation status was compared between Nepalese and Swedish patients and correlated with clinicopathological parameters. Nepalese and Swedish patients displayed equal levels of and methylation in tumors, but Nepalese patients exhibited a significantly higher level of methylation in mucosa compared to Swedish patients (p=0.0008). Moreover, a greater proportion of Nepalese patients showed methylation in mucosa compared to Swedish patients (31 vs. 2.6 %). Aberrant methylation of was also observed in the mucosa of Nepalese patients, characterized by high methylation at specific sites rather than uniform methylation across CpG sites. There were no significant differences in methylation levels based on tumor location among Nepalese patients, whereas Swedish patients exhibited higher methylation in right- compared to left-sided colon tumors. Swedish patients showed an increase in methylation in tumors with advancing age. Nepalese and Swedish patients displayed equal levels of and methylation in tumors. In contrast, Nepalese patients had a higher level of methylation as well as aberrant methylation of in mucosa compared to Swedish patients. These epigenetic differences may be linked to environmental and lifestyle factors. Ongoing research will further explore whether hypermethylation in the mucosa of Nepalese patients is associated with tumorigenesis and its potential utility in screening high-risk patients or predicting recurrence.