Epigenetic differences in the tumor suppressor genes MLH1 and p16INK4a between Nepalese and Swedish patients with colorectal cancer
Author:
Ghimire Bikal1ORCID, Kurlberg Göran2ORCID, Falk Peter23ORCID, Singh Yogendra1, Wettergren Yvonne23ORCID
Affiliation:
1. Department of GI and General Surgery , Maharajgung Medical Campus, Institute of Medicine, Tribhuvan University , Kathmandu , Nepal 2. Department of Surgery , Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden 3. Department of Surgery , Region Västra Götaland, Sahlgrenska University Hospital , Gothenburg , Sweden
Abstract
Abstract
Objectives
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 MLH1 and p16INK4a, comparing Nepalese and Swedish patients with CRC.
Methods
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 MLH1 promoter region and the first exon of p16INK4a 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.
Results
Nepalese and Swedish patients displayed equal levels of MLH1 and p16INK4a methylation in tumors, but Nepalese patients exhibited a significantly higher level of MLH1 methylation in mucosa compared to Swedish patients (p=0.0008). Moreover, a greater proportion of Nepalese patients showed MLH1 methylation in mucosa compared to Swedish patients (31 vs. 2.6 %). Aberrant methylation of p16INK4a 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 p16INK4a methylation in tumors with advancing age.
Conclusions
Nepalese and Swedish patients displayed equal levels of MLH1 and p16INK4a methylation in tumors. In contrast, Nepalese patients had a higher level of MLH1 methylation as well as aberrant methylation of p16INK4a 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.
Funder
The University of Gothenburg via the Global University Initiative The Swedish state under the LUA-ALF agreement The Ingabritt and Arne Lundberg Foundation
Publisher
Walter de Gruyter GmbH
Reference40 articles.
1. Sung, H, Ferlay, J, Siegel, R, Laversanne, M, Soerjomataram, I, Jemal, A, et al.. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49. 2. Mohandas, KM. Colorectal cancer in India: controversies, enigmas and primary prevention. Indian J Gastroenterol 2011;30:3–6. https://doi.org/10.1007/s12664-010-0076-2. 3. Brenner, H, Kloor, M, Pox, CP. Colorectal cancer. Lancet 2014;383:1490–502. https://doi.org/10.1016/S0140-6736(13)61649-9. 4. Bhurgri, Y, Khan, T, Kayani, N, Ahmad, R, Usman, A, Bhurgri, A, et al.. Incidence and current trends of colorectal malignancies in an unscreened, low risk Pakistan population. Asian Pac J Cancer Prev 2011;12:703–8. 5. Efremidou, EI, Liratzopoulos, N, Papageorgiou, SM, Romanidis, K, Tourlis, T, Kouklakis, G, et al.. Colorectal carcinoma: correlation between age, gender and subsite distribution. Chirurgia 2008;103:659–63.
|
|