Background & Aims: Unlike conventional adenomas, sessile serrated lesions (SSL) are common in both young and old individuals, but the BRAF mutant cancers arising occur predominantly in the eighth decade. DNA methylation changes accumulate as SSL become malignant. Lesser degrees of methylation also accumulate in normal tissues with age, leading to the concept of “epigenetic age”. Methylation is uncommon in SSL from young patients, suggesting epigenetic age of the intestine may modify the rate of BRAF induced methylation and thus SSL progression.
Methods: We used a conditional Braf mutant mouse model which develops intestinal hyperplasia followed by serrated adenomas and cancer. Genome-wide DNA methylation was assessed in the intestines with age. We then mutated Braf in young and aged mice for short time periods to compare the effect of age-related methylation on Braf induced methylation and tumorigenicity. Chronological and epigenetic age was also compared in human SSL.
Results: We observed a significant increase in intestinal epigenetic age in BrafV637E mice compared to wildtype littermates (P<0.0001). In mice aged to 9 months prior to Braf mutation there was a 10 fold relative risk of developing serrated adenomas compared to induction of Braf mutation at wean. Analysis of human SSL also suggested that BRAF induced methylation progresses more quickly in older individuals.
Conclusions: Our findings support a new conceptual model for serrated neoplasia whereby risk of progression is directly related to the epigenetic age of cells at the time of BRAF mutation, rather than the length of time since polyp initiation. This has implications for surveillance and chemopreventive strategies targeting the epigenome.