Impact of nucleotide excision repair ERCC2 and base excision repair APEX1 genes polymorphism and its association with recurrence after adjuvant BCG immunotherapy in bladder cancer patients of North India.
BACKGROUND
Altered DNA repair capacity due to polymorphisms in DNA repair genes may modify response to Bacillus Calmette-Guerin (BCG) immunotherapy for high risk superficial bladder cancer (SBC).We evaluated the prospective outcome of exicision repair cross complementing group 2 (ERCC2) and apurinic/apyriminidic endonuclease (APEX1) gene in tumor recurrence after BCG immunotherapy in SBC patients.


METHODS
The study included 135 SBC patients, of which BCG immunotherapy was received by 74 patients. Genotyping was performed for ERCC2 Asp(312)Asn (G > A), Lys751Gln (A > C), and APEX1 Asp(148)Glu (T > G) polymorphisms by restriction fragment length polymorphism PCR and amplification refractory mutation system (ARMS) methods.


RESULTS
Multiple Cox regression analysis demonstrated association of variant genotype of ERCC2 (312)AA polymorphism with high risk of recurrence in BCG treated patients (HR = 3.07, P = 0.016, P ( c ) = 0.048). Patients with the ERCC2 (312)AA polymorphic genotypes showed shorter recurrence free survival (log-rank, P = 0.005; AA/GA + AA = 14/44) who received BCG treatment. Overall, risk of recurrence in bladder cancer was observed with smokers and size of tumors (1-3 cm) (HR = 1.86, P = 0.023 and HR = 3.19, P = 0.031, respectively). Smokers were identified to be at elevated risk in BCG treated patients (HR = 2.84, P = 0.005). No association was observed with the (ERCC2 Lys(751)Gln and APEX1 Asp(148)Glu) polymorphisms and risk of recurrence.


CONCLUSIONS
Our data suggested variant (AA) of ERCC2 312 AA genotype to be associated with high risk of tumor recurrence and reduced recurrence free survival in superficial bladder cancer patients.
Gangawar
Ruchika
R
Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh 226014, India.
Ahirwar
Dinesh
D
Mandhani
Anil
A
Mittal
Rama Devi
RD
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000368:Aged; D001500:BCG Vaccine / Q000627:therapeutic use*; D016022:Case-Control Studies; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007194:India / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D051759:Xeroderma Pigmentosum Group D Protein; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C497292:ERCC2 protein, human