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Chromosomal instability (CIN), impaired telomere biology, and aberrant DNA methylation are implicated in colorectal cancer (CRC) development. Tracking these alterations from precancerous lesions through tumors to metastases may reveal biomarkers of CRC initiation and progression. Tissue samples from 44 patients with either high-grade colorectal dysplasia (HGA; n = 13) or advanced metastatic CRC (n = 31) were analyzed. CIN was assessed in all patients using either low-coverage whole-exome sequencing or microarray-based comparative genomic hybridization. In a subset of patients, genome-wide CpG methylation profiling (n = 19) and telomere length measurements (n = 15) were performed. CIN was detected in 85% of HGA patients, spanning focal CNVs in MALAT1 (46%) to recurrent alterations on chromosomes 11, 13, and 20, with PTK6 being the most frequently amplified (61%). CIN was comparable between primary tumors and synchronous metastases but was significantly elevated in metachronous cases. DEK was amplified in all metastases but the aberration was absent in primaries, irrespective of tissue chronicity. Methylation profiling distinguished HGA from adjacent non-dysplastic mucosa (9859 differentially methylated CpGs) and unrelated tumor tissues (17 638 CpGs), whereas primary tumors and metastases differed at only five CpG sites. Both primary tumors and metastases appeared epigenetically younger than colonic mucosa. Metastases exhibited significantly shorter telomeres than both primary tumors (P = .019) and colonic mucosa (P = .001). The amplification of PTK6 may serve as an early biomarker detectable at the HGA stage, while DEK amplification appears crucial for metastatic progression and may represent a therapeutic target. Further validation is needed.