Polymorphisms of the human NRAMP1 gene are associated with response to bacillus Calmette-Guerin immunotherapy for superficial bladder cancer.
OBJECTIVE
Superficial bladder tumors have a high recurrence rate and 10% to 20% of recurrences progress to invasive cancer. Recurrence and progression can best be prevented by nonspecific immunotherapy using intravesical BCG instillations. The NRAMP1 gene has been implicated in susceptibility to infectious and autoimmune diseases, and in response to BCG in murine models. We evaluated the association of 5 NRAMP1 gene polymorphisms with the risk of superficial bladder cancer recurrence and response to immunotherapy.


METHODS
The (GT)n, 274 C/T, 469 + 14 G/C, 1465-85 G/A and D534N polymorphisms were tested on peripheral blood DNA of individuals from three cohorts: 37 bladder tumor patients treated by transurethral resection and without recurrence after up to eight years, 67 patients at high risk of recurrence of their bladder tumors and treated with BCG and 109 controls, using restriction fragment length polymorphisms or microsatellite analysis following PCR amplification.


RESULTS
The D543N G:A genotype was found more frequently in patients at high risk of recurrence (8 of 67 or 12%) than in controls (2 of 109 or 2%) (p = 0.007). Patients with nonrecurrent tumors showed no difference with controls (1 of 37 or 3%) (p = 1.0). Moreover, in multivariate and survival analyses, both D543N and (GT)n polymorphisms showed association with recurrence-free survival in the cohort of patients at high risk of recurrence, following BCG treatment.


CONCLUSIONS
These data suggest the implication of the NRAMP1 gene in bladder cancer recurrence and response to BCG immunotherapy.
Decobert
Marc
M
Centre de Recherche en Cancérologie de Université Laval, Québec, Canada.
Larue
Hélène
H
Bergeron
Alain
A
Harel
François
F
Pfister
Christian
C
Rousseau
François
F
Lacombe
Louis
L
Fradet
Yves
Y
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000368:Aged; D000369:Aged, 80 and over; D001500:BCG Vaccine / Q000627:therapeutic use*; D027682:Cation Transport Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D011110:Polymorphism, Genetic; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D000099173:Natural Resistance-associated Macrophage Protein 1
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D027682:Cation Transport Proteins; D000099173:Natural Resistance-associated Macrophage Protein 1