Genome-wide DNA methylation profiles of colorectal tumors in Lynch syndrome and familial adenomatous polyposis.

Abstract

Background: Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are hereditary cancer predisposing syndromes characterized by increased risk of especially early-onset colorectal cancer. Predisposition to LS is caused by germline mutations in DNA mismatch repair genes leading to elevated cancer progression and microsatellite instability. FAP is associated with germline mutations in APC promoting cancer initiation and chromosomal instability. DNA methylation is an important epigenetic mechanism in early tumorigenesis via, e.g., field defects in non-neoplastic colon. Our aim was to study genome-wide methylation changes in colorectal specimens (adenomas and carcinomas supplemented with paired normal colon) obtained during colonoscopy surveillance, and explore the role of such alterations in tumorigenesis, with a special focus on early changes. To our best knowledge, this study is the first one to compare altered DNA methylation genome-wide in LS and FAP-associated colorectal neoplasia.

Results: DNA methylation alterations were subtle in FAP adenomas, whereas in LS adenomas, changes were abundant when compared to their normal counterparts. When FAP normal and LS normal colon were compared, DNA methylation changes of FAP normal colon mirrored those occurring in LS tumors, suggesting that colorectal tumorigenesis-associated DNA methylation alterations take place already in FAP normal colon mucosa. DNA methylation age was more variable in LS than FAP normal colon, and in proximal than distal colon, when compared to individuals' age at the time of sampling. In LS tumors, DNA methylation changes (hyper- and hypomethylation) were abundant even in adenomas with low-grade dysplasia and stable microsatellites and peaked in adenomas with high-grade dysplasia. LINE-1 hypomethylation was more prominent in LS adenomas than FAP adenomas, but normal colon of LS and FAP displayed similar levels of LINE-1 methylation.

Conclusions: Genome-wide DNA methylation changes are an integral part of FAP and LS-associated colorectal tumorigenesis. Occurrence at early stages, even in non-neoplastic colonic mucosa, and increased prevalence with progressive dysplasia suggest a role in tumor development. Overlap of many of the topmost DNA methylation alterations between LS and FAP, and previous reports of their occurrence in sporadic colorectal and other tumors as well, imply their broad biological relevance and possible biomarker potential for clinical applications.