Current evidence supporting associations of DNA methylation measurements with survivorship burdens in cancer survivors: A scoping review

Abstract

Introduction: Identifying reliable biomarkers that reflect cancer survivorship symptoms remains a challenge for researchers. DNA methylation (DNAm) measurements reflecting epigenetic changes caused by anti-cancer therapy may provide needed insights. Given lack of consensus describing utilization of DNAm data to predict survivorship issues, a review evaluating the current landscape is warranted.

Objective: Provide an overview of current studies examining associations of DNAm with survivorship burdens in cancer survivors.

Methods: A literature review was conducted including studies if they focused on cohorts of cancer survivors, utilized peripheral blood cell DNAm data, and evaluated the associations of DNAm and survivorship issues.

Results: A total of 22 studies were identified, with majority focused on breast (n = 7) or childhood cancer (n = 9) survivors, and half studies included less than 100 patients (n = 11). Survivorship issues evaluated included those related to neurocognition (n = 5), psychiatric health (n = 3), general wellness (n = 9), chronic conditions (n = 5), and treatment specific toxicities (n = 4). Studies evaluated epigenetic age metrics (n = 10) and DNAm levels at individual CpG sites or regions (n = 12) for their associations with survivorship issues in cancer survivors along with relevant confounding factors. Significant associations of measured DNAm in the peripheral blood samples of cancer survivors and survivorship issues were identified.

Discussion/conclusion: Studies utilizing epigenetic age metrics and differential methylation analysis demonstrated significant associations of DNAm measurements with survivorship burdens. Associations were observed encompassing diverse survivorship outcomes and timeframes relative to anti-cancer therapy initiation. These findings underscore the potential of these measurements as useful biomarkers in survivorship care and research.

Keywords: cancer survivorship; differential DNA methylation; epigenetic aging; epigenetics; literature review; multivariate modeling; study design.

FIGURE 1

Literature search process. The flowchart describes the process identifying studies for inclusion in this review. First potential studies were identified using keyword searches in PubMed, then studies were excluded based on preliminary title screening and publication type, followed by subsequent abstract screening. Studies were included in the study meeting inclusion criteria both from literature search and manual search techniques.

FIGURE 2

Study population and study design characteristics. The y‐axis represents study population size in a log 10 scale, with the x‐axis representing study citation number. The coloration of bars represents cancer population type, with asterisks (*) over bars identifying longitudinal studies. Studies to the left of the black line are those utilizing differential methylation analysis while those to the right are utilizing epigenetic aging analysis.

FIGURE 3

Heatmaps showing covariates utilized in multivariate analysis with methylation data. For panels A and B, column 1 represents the citation number for each row as identified in Table S2. Each subsequent column represents a potential covariate utilized and each row represents a study within the review. Boxes within the heatmap having red coloration indicate the study utilized a covariate, while blue boxes indicate a study did not. Panel A shows covariates utilized in epigenetic age analysis studies, while panel B shows covariates utilized in differential methylation analysis studies. Relevant abbreviations utilized within the figure include: BCP, blood cell proportions; BMI, body mass index; Chemo, chemotherapy received; Comorbid, comorbidities; HPV, human papilloma virus.