IGFBP-3 gene methylation in primary tumor predicts recurrence of stage II colorectal cancers

Objectives: To evaluate the influence of IGFBP-3 methylation on recurrence in patients with stage II colorectal cancer (CRC) from 2 independent cohorts. Background: The relationship between IGFBP-3 methylation in primary tumors (PTs) or lymph nodes (LNs) and risk of recurrence in patients with stage II CRC treated with surgery alone is unknown. Methods: IGFBP-3 methylation of DNA from 115 PTs and 1641 LNs in patients with stage II CRC from 2 independent cohorts was analyzed. Forty patients developed recurrence, whereas 75 matched patients remained recurrence free for more than 2 years after surgery. Cox proportional hazard models were used to calculate hazard ratios (HRs) of recurrence, adjusted for patient and tumor characteristics. Results: Methylation of IGFBP-3 in PTs was identified to be significantly associated with risk of recurrence in the training set. The signature was tested in a validation set and classified 40.7% of patients as high risk. Five-year recurrence-free survival rates were 76.4% and 58.3% for low-and high-risk patients, respectively, with an HR of 2.21 (95% confidence interval, 1.04- 4.68; P = 0.039). In multivariate analysis, the signature remained the most significant prognostic factor, with an HR of 2.40 (95% confidence interval, 1.10-5.25; P = 0.029). A combined analysis of 1641 LNs from the 2 sets identified IGFBP-3 methylation in LNs was not associated with risk of recurrence. Conclusions: Detection of IGFBP-3 methylation in PTs, but not in LNs, provides a powerful tool for the identification of patients with stage II CRC at high risk of recurrence.