Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications
Abstract
:1. Introduction
2. DNA Methylation in Cancer
2.1. Biology of DNA Methylation in Malignancy
2.1.1. Aberrant DNA Methylation of CpG Islands Are Seen in Cancer
2.1.2. Gene Promoter Hypermethylation Leads to Silencing of Tumor Suppressor Genes
2.1.3. Methylation Can Lead to Epigenetic Activation of Oncogenic Pathways
2.1.4. Global DNA Hypomethylation Leads to Chromosomal Instability
2.1.5. DNA Methylation Influences Gene Expression beyond Promoter Silencing
2.1.6. Methylation Can Influence the Non-Coding Genome, Leading to Cancer
2.1.7. Role of DNA Methylation in the Tumor Microenvironment
2.2. Cell-Free Tumor Methylome Recapitulates the Cancer Epigenome
2.3. Applications of cfDNA Methylation as Biomarker in Cancer
2.3.1. Methylation as a Diagnostic Biomarker
2.3.2. Methylation as a Prognostic Biomarker of Patient Outcomes
2.3.3. Methylation as a Predictive Biomarker of Treatment Response
2.3.4. Minimal Residual Disease
3. Challenges and Future Directions
3.1. DNA Methylation in Oncology
3.2. Liquid Biopsy in Oncology
3.3. ctDNA Methylation as a Biomarker in Oncology
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A. Narrative Review Search Strategy
References
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Application | Cancer | Test/Assay/Target | Study Size (N) | Sensitivity | Specificity | Comments | References |
---|---|---|---|---|---|---|---|
Diagnosis | Colon | Epi proColon®/methylation specific PCR/SEPT9 | 245 | 67% (95% CI: 56–77%) | 89% (95% CI: 83–93%) | Obtained FDA approval in 2016 | [77] |
Diagnosis | Lung | Epi proLung®/methylation specific PCR/SHOX2 and PTGER4 | 172 | AUROC = 0.88; at specificity = 90%, sensitivity = 67%; at sensitivity = 90%, specificity = 73%. | Obtained CE-IVD mark in 2017 | [79] | |
Diagnosis | Colon | EarlyTect® Colon/methylation-specific PCR/SCD2 | 256 | 87.0% (95% CI: 80.0–92.3%) | 95.2% (95% CI: 89.8–98.2%) | -- | [80] |
Diagnosis | Lung | EarlyTect® Lung Cancer/methylation-specific PCR/PCDHGA12 | -- | 75.0% (95% CI: 61.8–81.8%) | 78.9% (95% CI: 62.2–89.8%) | In development for use with bronchial washings or blood | [90] |
Diagnosis (MCED) | Pan-cancer | GRAIL(Galleri™)/NGS and custom classifier/ methylation panel covering 1.1 × 106 CpGs | 4077 | 51.5% (95% CI: 49.6–53.3%) | 99.5% (95% CI: 99.0–99.8%) | Data based on CCGA trial (NCT02889978) | [91] |
MRD | Pan-cancer | Guardant Reveal™/NGS and custom classifier/500 genes and 4Mb of DMRs | CRC cohort = 84; Breast cancer cohort = 20 | CRC cohort: 55.6% (95% CI: 35.3–74.5) Breast cancer cohort: sensitivity = 85% 1 | CRC cohort: 100% (95% CI: 90.5–100) Breast cancer cohort: specificity = 100% 1 | -- | [92,93] |
Diagnosis (MCED)/Prognosis/MRD | Pan-cancer | ADELA/cfMeDIP-seq/whole genome | MCED = 4322 Prognosis: HNSCC cohort = 93; RCC cohort = 151 | MCED: Multi-cancer cohort—Cancer cases discriminated from controls with an AUROC of 0.94 (95% CI: 0.93, 0.96). In low cfDNA shedding tumors, AUROC was 0.92 (95% CI: 0.91, 0.94). Prognosis: HNSCC—Likelihood of recurrence or progression (HR 3.51, 95% CI: 1.1–11.19, p = 0.034); RCC—Likelihood of recurrence or progression (HR 13.28, 95% CI: 5.47–32.26, p < 0.001) | MRD assay currently in development | [88,94,95] |
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Sacdalan, D.B.; Ul Haq, S.; Lok, B.H. Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications. Curr. Oncol. 2024, 31, 482-500. https://doi.org/10.3390/curroncol31010033
Sacdalan DB, Ul Haq S, Lok BH. Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications. Current Oncology. 2024; 31(1):482-500. https://doi.org/10.3390/curroncol31010033
Chicago/Turabian StyleSacdalan, Danielle Benedict, Sami Ul Haq, and Benjamin H. Lok. 2024. "Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications" Current Oncology 31, no. 1: 482-500. https://doi.org/10.3390/curroncol31010033