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Ann Surg. 2016 Feb;263(2):337-44. doi: 10.1097/SLA.0000000000001204.

IGFBP-3 Gene Methylation in Primary Tumor Predicts Recurrence of Stage II Colorectal Cancers.

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*Department of Gastrointestinal Surgery, Daping Hospital, Third Military Medical University, Chongqing, China †Department of Surgery ‡Department of Oncology, The Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD §Department of Pathology and David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY.



To evaluate the influence of IGFBP-3 methylation on recurrence in patients with stage II colorectal cancer (CRC) from 2 independent cohorts.


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.


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.


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.


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.

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