Novel Methylated DNA Markers in the Surveillance of Colorectal Cancer Recurrence

Novel Methylated DNA Markers in the Surveillance of Colorectal Cancer Recurrence:

Purpose: We aimed to assess the concordance of colorectal cancer (CRC)-associated methylated DNA markers (MDMs) in primary and metastatic CRC for feasibility in detection of distantly recurrent/metastatic CRC in plasma. Experimental Design: A panel of previously discovered CRC-associated MDMs was selected. MDMs from primary and paired metastatic CRC tissue were assayed with quantitative methylation-specific PCR. Plasma MDMs were measured blindly by target enrichment long-probe quantitative amplified signal assays. Random forest modeling was used to derive a prediction algorithm of MDMs in archival plasma samples from primary CRC cases. This algorithm was validated in prospectively collected plasma samples from recurrent CRC cases. The accuracy of the algorithm was summarized as sensitivity, specificity, and area under the curve (AUC). Results: Of the 14 selected MDMs, the concordance between primary and metastatic tissue was considered moderate or higher for 12 MDMs (86%). At a preset specificity of 95% (91-98%), a panel of 13 MDMs in plasma from 97 CRC cases and 200 controls detected stage IV CRC with 100% (80-100%) sensitivity and all stages of CRC with an AUC 0.91 (0.87-0.95), significantly higher than CEA (AUC 0.72 (0.65-0.79)). This panel in plasma from 40 cases, and 60 healthy controls detected recurrent/metastatic CRC with 90% (76-97%) sensitivity with specificity of 90% (79-96%) and an AUC of 0.96 (0.92-1).The panel was positive in 0.30 (0.19-0.43) of 60 patients with no evidence of disease post-operative CRC patients. Conclusions: Plasma assay of novel CRC-associated MDMs can reliably detect primary CRC and distantly recurrent CRC with promising accuracy.