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The epigenetic deregulation of CpG islands (CGIs) plays a crucial role in cancer initiation and progression. CGIs comprise 1%-2% of the human genome and are rich in differentially methylated regions (DMRs) that can serve as biomarkers in clinical samples and liquid biopsies. Focusing epigenetic sequencing on CpG-rich regions, including CGIs, while avoiding non-informative sequences, offers an efficient and sensitive approach for cancer detection and monitoring, especially in samples with excess normal DNA. To this end, we developed adaptor-anchored methylation amplification via proximity primers (aMAPPs), a versatile PCR-based enrichment method. Proximity primers (PPs) are specially designed primers that amplify either methylated or unmethylated proximal CpGs, depending on the selected methylation conversion method. aMAPP achieves high-coverage of genome-wide CGIs and detects numerous DMRs in tumor samples compared to adjacent normal tissue using ultra-low depth sequencing (∼300 000 reads). aMAPP enables detection of aberrant methylation down to 0.01% allelic frequency in tumor DNA dilutions and cell-free DNA, requires only picogram DNA input, and can be adapted to enrich either small panels of cancer-specific DMRs or large genomic-fractions including >90% of genomic CGIs. Overall, aMAPP provides a simple, cost-effective, and highly sensitive strategy for capturing the epigenetic footprint of genome-wide CpGs and identifying aberrant methylation events.