Significance of FANCJ expression as a predictive marker of sensitivity to 5-fluorouracil in colorectal cancer.

Abstract

10618 Background: Fanconi anemia protein, FANCJ, directly interacts with MLH1, a key protein involved in the DNA mismatch repair process. Deficient mismatch repair, or microsatellite instability, is a marker for the ineffectiveness of 5-fluorouracil (5-FU) and positive prognosis of colorectal cancer (CRC). We investigated the significance of FANCJ expression in CRC, focusing on the effects of 5-FU-based adjuvant chemotherapy. Methods: Clinicopathologic features and immunohistochemical expression of FANCJ and MLH1 were studied in 219 patients with CRC. We also analyzed 5-FU sensitivity in CRC cell lines with varying levels of FANCJ expression. Results: FANCJ expression was elevated in tumor tissues compared with normal epithelial tissue (p<0.001). High expression of FANCJ was significantly associated with 5-FU resistance measured by the succinate dehydrogenase inhibition test (p=0.02) and poor recurrence-free survival (RFS) (p=0.03). Among patients with stage II/III tumors who received 5-FU, patients with tumors exhibiting high FANCJ expression had significantly worse RFS than patients with tumors exhibiting low FANCJ expression (p=0.01). Among patients who did not receive adjuvant chemotherapy, FANCJ expression was not correlated with RFS (p=0.76). High FANCJ expression was correlated with 5-FU resistance in tumors with normal MLH1 expression (p=0.01), but not in tumors not expressing MLH1 (p=0.67). In vitro, FANCJ overexpression was correlated with 5-FU resistance in MLH1-proficient HCT116 3-6 cells, but not in MLH1-deficient HCT116 cells. Conclusions: FANCJ could be a useful biomarker to predict the response to 5-FU and prognosis of CRC, particularly in tumors with normal MLH1 expression.