Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor.
OBJECTIVE
Genetic and epigenetic alterations play an important role in urothelial cancer pathogenesis. Deeper understanding of these processes could help us achieve better diagnosis and management of this life-threatening disease. The aim of this research was to evaluate the methylation status of selected tumor suppressor genes for predicting BCG response in patients with high grade non-muscle-invasive bladder tumor (NMIBC).


METHODS
We retrospectively evaluated 82 patients with high grade non-muscle-invasive bladder tumor (stage Ta, T1, CIS) who had undergone BCG instillation therapy. We compared epigenetic methylation status in BCG-responsive and BCG-failure groups. We used the MS-MLPA (Methylation-Specific Multiplex Ligation-Dependent Probe Amplification probe sets ME001 and ME004. The control group was 13 specimens of normal urotel (bladder tissue)).


RESULTS
Newly identified methylations in high grade NMIBC were found in MUS81a, NTRK1 and PCCA. The methylation status of CDKN2B (P=0.00312**) and MUS81a (P=0.0191*) is associated with clinical outcomes of BCG instillation therapy response. CDKN2B and MUS81a unmethylation was found in BCG failure patients.


CONCLUSIONS
The results show that the methylation status of selected tumor suppressor genes (TSGs) has the potential for predicting BCG response in patients with NMIBC high grade tumors. Tumor suppressor genes such as CDKN2b, MUS81a, PFM-1, MSH6 and THBS1 are very promising for future research.
Department of Urology, Faculty of Medicine in Hradec Kralove, Charles University in Prague and University Hospital in Hradec Kralove, Czech Republic.
Petr
P
Husek
Department of Urology, Faculty of Medicine in Hradec Kralove, Charles University in Prague and University Hospital in Hradec Kralove, Czech Republic.
Jaroslav
J
Pacovsky
Institute of Clinical Biochemistry and Diagnostics, Faculty of Medicine in Hradec Kralove, Charles University in Prague and University Hospital in Hradec Kralove, Czech Republic.
Marcela
M
Chmelarova
The Fingerland Department of Pathology, Faculty of Medicine in Hradec Kralove, Charles University in Prague and University Hospital in Hradec Kralove, Czech Republic.
Miroslav
M
Podhola
Department of Urology, Faculty of Medicine in Hradec Kralove, Charles University in Prague and University Hospital in Hradec Kralove, Czech Republic.
Milos
M
Brodak
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001500:BCG Vaccine / Q000627:therapeutic use*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D012189:Retrospective Studies; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics*
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D001500:BCG Vaccine
BCG; CDKN2b; bladder cancer; methylation