Polyamine-modulated factor-1 methylation predicts Bacillus Calmette-Guérin response in patients with high-grade non-muscle-invasive bladder carcinoma.
BACKGROUND
Bacillus Calmette-Guérin (BCG) is a standard treatment to reduce tumor recurrence and delay progression of high-risk non-muscle-invasive (NMI) bladder tumors. However, it is not clear yet which patients are more likely to respond to BCG.


OBJECTIVE
The aim was to evaluate the role of polyamine-modulated factor-1 (PMF-1) methylation in predicting clinical outcome of T1 high-grade (T1HG) bladder tumors treated with BCG.


METHODS
In a retrospective design, PMF-1 methylation was analyzed on tumor specimens belonging to 108 patients with T1HG NMI bladder cancer undergoing BCG treatment. Median follow-up was 77 mo (range: 5-235 mo).


METHODS
PMF-1 methylation was assessed by methylation-specific polymerase chain reactions. Recurrence, progression into muscle-invasive tumors, and disease-specific survival rates were analyzed using competing risks regression analysis.


CONCLUSIONS
Among the 108 patients analyzed, 35 had recurring disease (32.4%), 21 progressed (19.4%), and 16 died of disease (14.8%); 71.3% of tumors had PMF-1 methylation. Univariate analyses using cumulative incidence curves revealed that an unmethylated PMF-1 was significantly associated with increased recurrence (p=0.026), progression (p=0.01), and shorter disease-specific survival (log-rank, p=0.03). Multivariate analyses indicated that among sex, age, focality, tumor size, and concomitant carcinoma in situ, only PMF-1 methylation provided significant hazard ratios (HRs) for recurrence of (HR: 2.032; p=0.042), and progression (HR: 2.910; p=0.020). Limitations of the study include its retrospective design, lymphovascular invasion status not available, short maintenance BCG, and that a second transurethral resection was not performed.


CONCLUSIONS
Epigenetic analyses revealed that the methylation status of PMF-1 was associated with the clinical outcome of patients with T1HG tumors undergoing BCG treatment. An unmethylated PMF-1 correlated to recurrence and progression in T1HG disease using univariate and multivariate analyses. Thus, assessing the methylation status of PMF-1 may serve to distinguish patients responding to BCG from those who may require more aggressive therapeutic approaches.
Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain.
Miguel
M
Alvarez-Múgica
Jesus M
JM
Fernández-Gómez
Virginia
V
Cebrian
Florentino
F
Fresno
Safwan
S
Escaf
Marta
M
Sánchez-Carbayo
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000283:Administration, Intravesical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001500:BCG Vaccine / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013030:Spain; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; C120655:PMF1 protein, human; D014157:Transcription Factors