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. 2025 Aug 2;17(1):137.
doi: 10.1186/s13148-025-01940-x.

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

Affiliations

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

Satu Mäki-Nevala et al. Clin Epigenetics. .

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.

Keywords: Colon adenoma; Colorectal cancer; DNA methylation; Familial adenomatous polyposis; Lynch syndrome; Tumorigenesis.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki. All biopsies were taken after patients’ informed consent. The study was approved by the Institutional Review Boards of the Central Finland Health Care District (Dnro 10U/2011, 3.5.2011) and the Helsinki and Uusimaa Health Care District (HUS/390/2021, 23.2.2022). Consent for publication: Not applicable. Competing interests: T.T.S. reports consultation fees from Amgen Finland, Tillots Pharma and Nouscom, being a co-owner and CEO of Healthfund Finland Ltd, and a position in the Clinical Advisory Board and a minor shareholder of Lynsight Ltd. P.P. reports a position in the Clinical Advisory Board of Lynsight Ltd. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study design. Colorectal adenomas (Ad) and carcinomas (CRC) were collected from colonoscopy surveillance of LS and FAP carriers and included in molecular analyses shown (see Methods below for details)
Fig. 2
Fig. 2
LINE-1 methylation across the samples, averaged hypermethylation of tumorous samples, and TMB of LS tumors. A LINE-1 methylation across all the samples. Kruskal–Wallis test was applied on averaged LINE-1 methylation β values of each sample group (P = 7.7e−09). Pairwise comparisons were studied using the Wilcoxon test and BH-adjusted P values < 0.05 are presented in the figure. B Averaged β values of hypermethylated probes (see Materials and Methods, and Results) in LS and FAP tumor samples. Kruskal–Wallis test was applied on all the sample groups, and Wilcoxon test for pairwise comparisons of LS tumor sample groups were applied, but all BH-adjusted P values were > 0.05. C LINE-1 methylation levels in LS normal and MSS and MSI adenomas with low-grade dysplasia. Kruskal–Wallis test was applied on all the samples (P = 3.69e−06). Pairwise comparisons were studied using the Wilcoxon test and BH-adjusted P values < 0.05 are presented in the figure. D Averaged β values of hypermethylated probes (see Materials and Methods, and Results) in MSS and MSI LS adenomas with low-grade dysplasia. In the boxplots, the upper and lower edges of the boxes indicate the 75th and 25th percentiles, the horizontal line inside the box denotes the median, and the whiskers indicate the lowest and highest values (outliers are shown outside the whiskers). Each sample’s averaged β value is indicated as a single dot. E LINE-1 methylation level compared to averaged hypermethylation in LS and FAP tumors using the Spearman’s correlation test. F TMB compared to LINE-1 methylation level in LS tumors using the Spearman-correlation test. G. TMB compared to averaged hypermethylation in LS tumors using the Spearman’s correlation test. The shaded areas represent 95% confidence intervals
Fig. 3
Fig. 3
DNAm age and age at the sampling. A DNAm age compared to age at the sampling in LS normal, LS unaffected normal, and FAP normal samples. Black line denotes the bisector line when y = x. B DNAm age compared to age at the time of tissue sampling in LS normal samples divided into proximal and distal samples. C DNAm age compared to age at the sampling in LS unaffected normal samples divided into proximal and distal samples. D DNAm age compared to age at the sampling in distal samples of LS normal and FAP normal. Each sample’s averaged β value is indicated as a single dot
Fig. 4
Fig. 4
An overview of DMPs in LS and FAP tumors and their relation to CpG island and gene regions. Red color indicates hypermethylated probes and blue stands for hypomethylated probes. DMPs in A LS adenomas with low-grade dysplasia, LS adenomas with high-grade dysplasia, and LS carcinomas were compared to LS normal samples, and FAP adenomas were compared to FAP normal samples. B Overview of DMPs and their relation to gene regions
Fig. 5
Fig. 5
Volcano plots of DMPs in LS tumors (AC) and FAP adenomas (D). Adjusted P values are plotted against averaged β-values (Diff_avgBeta). Hypermethylated probes in tumors compared to normal counterparts are represented with positive averaged β-values and hypomethylated probes in tumors with negative values. Red dots indicate the DMPs above both thresholds marked with dashed lines (|Δ averaged β|> 0.15 and BH-adjusted −Log10 P > 2, i.e. P value < 0.01)

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