Background: Colorectal cancer (CRC) is the fourth most common cancer in UK. Obesity is a major modifiable risk factor for CRC. The LEP gene encodes the leptin hormone which is a key regulator of body weight. LEP is overexpressed in the colorectal mucosa of patients with CRC and may contribute to the development and progression of CRC. This study investigated the effects of weight loss induced by bariatric surgery (BS) on LEP gene methylation in rectal mucosal samples.
Methods: Rectal mucosal samples were collected at 10 cm from the anal verge using sigmoidoscopy from participants in the Biomarkers of Colorectal cancer After Bariatric Surgery (BOCABS) study before and 6 months after bariatric surgical intervention and from a healthy Control group. Methylation at 4 CpG sites within the LEP gene in DNA from rectal mucosal biopsies was quantified using pyrosequencing (Qiagen Pyromark Q96 ID).
Results: DNA was extracted from rectal mucosal samples from 19 surgery participants (46.7 years old, 4 males) and 9 Controls (48.5 years old, 4 males). At 6 months post-surgery, mean BMI in participants fell from 42.9 to 33.1 (P<0.001) but remained lower that that in the Control group (25.3).
Before surgery, methylation of LEP was higher at all CpG sites in Controls than in participants with obesity (mean for all sites: 45.5% vs 53.9%, P=0.001).
After weight loss surgery, mean LEP methylation across all CpG sites increased significantly (P=0.005) and there were significant increases at the 1st (P=0.003), 3rd (P=0.005), and 4th (P=0.001) CpG sites. However, methylation remained lower than in Controls.
Conclusion: In individuals who were obese, weight loss following bariatric surgery tends to normalise methylation of the LEP gene. Since DNA methylation contributes to regulation of gene expression, the effects of this change in change in methylation on expression of LEP, and whether this epigenetic change relates to the protective effect of weight loss on lowering CRC risk, remain to be determined.
Keywords: Colorectal cancer, DNA methylation, LEP
12 Sep 2019 - 13 Sep 2019