The prognostic role of circulating tumour DNA detected prior to clinical diagnosis of colorectal cancer in the HUNT study

BACKGROUND: Today, the prognostic tools available at the time of diagnosis in colorectal cancer (CRC) are limited. Better prognostic tools are a prerequisite for personalised treatment. This study aimed to investigate whether circulating tumour DNA (ctDNA) markers found in plasma before clinical diagnosis of CRC could contribute to the prediction of poor prognosis. METHODS: This observational cohort study included patients diagnosed with CRC stage I-III within 24 months following participation in the Trøndelag Health Study (n = 85). Known methylated ctDNA biomarkers of CRC were analysed by PCR in plasma. Outcomes were overall survival (OS), recurrence-free survival (RFS) and poor prognosis (PP). Candidate clinical and methylated ctDNA predictors of the outcomes were identified by Cox regression analyses. RESULTS: Methylated GRIA4 (HR 1.96 (1.06-3.63)), RARB (HR 9.48 (3.00-30.00)), SLC8A1 (HR 1.97 (1.03-3.77)), VIM (HR 2.95 (1.22-7.14)) and WNT5A (HR 5.83 (2.33-14.56)) were independent predictors of OS, methylated RARB (HR 9.67 (2.54-36.81)), SDC2 (HR 3.38 (1.07-10.66)), SLC8A1 (HR 2.93 (1.01-8.51)) and WNT5A (HR 6.95 (1.81-26.68)) were independent predictors of RFS and methylated RARB (HR 6.11 (1.69-22.18)), SDC2 (HR 2.79 (1.20-6.49)) and WNT5A (HR 5.57 (3.04-15.26)) were independent predictors of PP (p < 0.05). CONCLUSIONS: Prediagnostic ctDNA markers are promising contributors to predicting poor prognosis in CRC, potentially becoming one of the tools guiding more personalised treatment.