The significance of aberrant CHFR methylation for clinical response to microtubule inhibitors in gastric cancer.
BACKGROUND
We studied the correlations between CHFR (checkpoint with FHA and RING finger) gene methylation and responses to microtubule inhibitors (MI) in gastric cancer.


METHODS
We examined 9 gastric cancer cell lines and 46 gastric cancer specimens from patients who underwent surgical resection. Promoter methylation was determined by methylation-specific polymerase chain reaction (MSP). CHFR mRNA expression was estimated by quantitative reverse transcription-PCR. The MI-induced growth inhibition was assayed by a standard MTT method.


RESULTS
CHFR expression was silenced by aberrant promoter methylation in 3 of 9 gastric cancer cell lines. The level of CHFR mRNA expression was closely correlated with IC(50) in the MI-treated cells (R=0.889, P=0.005). In 46 patients with gastric cancers, 24 (52%) presented aberrant CHFR methylation. Among them, 12 patients had received treatment with MI because of advanced-stage tumor or tumor recurrence after surgery. The responders to the MI treatment were 29% in patients with CHFR methylation and 20% in those without the methylation. However, 6 (86%) of 7 patients with methylated CHFR tumor showed some regression or no progression, whereas 4 (80%) of 5 patients with unmethylated CHFR tumor manifested progressive deterioration.


CONCLUSIONS
These observations indicated that CHFR methylation may be a clinically useful approach to predict the responsiveness of gastric cancers to treatment with MI.
Department of Surgery, Saga University Faculty of Medicine, Nabeshima 5-1-1, Saga 849-8501, Japan.
Yasuo
Y
Koga
Yoshihiko
Y
Kitajima
Atsushi
A
Miyoshi
Ken
K
Sato
Seiji
S
Sato
Kohji
K
Miyazaki
D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D050257:Tubulin Modulators / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases
D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D050257:Tubulin Modulators; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases