FANCJ expression predicts the response to 5-fluorouracil-based chemotherapy in MLH1-proficient colorectal cancer

Ann Surg Oncol. 2012 Oct;19(11):3627-35. doi: 10.1245/s10434-012-2349-8. Epub 2012 Apr 12.

Abstract

Purpose: Fanconi anemia protein, FANCJ, directly interacts with MLH1, a key protein involved in DNA mismatch repair. Deficient mismatch repair, or microsatellite instability, is a potent marker for the ineffectiveness of 5-fluorouracil (5-FU) in 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. High expression of FANCJ was significantly associated with 5-FU resistance measured by the SDI test (P < 0.05) and poor recurrence-free survival (RFS) (P < 0.05). Among patients with stage II/III tumors who received 5-FU, patients with tumors exhibiting high FANCJ expression had significantly worse RFS than did 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 < 0.05) but not in tumors not expressing MLH1 (P = 0.9). 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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aged
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Proliferation
  • Chemotherapy, Adjuvant
  • Chi-Square Distribution
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / surgery
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • Fanconi Anemia Complementation Group Proteins / genetics
  • Fanconi Anemia Complementation Group Proteins / metabolism*
  • Female
  • Fluorouracil / therapeutic use*
  • HCT116 Cells
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Microsatellite Instability
  • Middle Aged
  • MutL Protein Homolog 1
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proportional Hazards Models
  • Retrospective Studies
  • Transcription, Genetic
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Antimetabolites, Antineoplastic
  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • Biomarkers, Tumor
  • Fanconi Anemia Complementation Group Proteins
  • MLH1 protein, human
  • Nuclear Proteins
  • MutL Protein Homolog 1
  • Fluorouracil