Polymorphisms in NQO1 and the clinical course of urinary bladder neoplasms.
OBJECTIVE
Urinary bladder neoplasms differ considerably in biological potential, and tumor morphology alone cannot predict their clinical behaviors. Polymorphisms in xenobiotic metabolic genes reportedly modulate susceptibility to bladder neoplasms and may affect the clinical course and outcomes of the disease. This study was conducted to determine the effect of polymorphisms in the xenobiotic metabolic genes on the disease course and clinical outcomes of urinary bladder neoplasms.


METHODS
Patients with urinary bladder neoplasms who had been followed up for a 5-year period were genotyped for NQO1 (R139W, P187S), NAT (rapid/slow), GSTP1 (I105V), GSTT1 and GSTM1 (non-null/null) and MTHFR (A222V, E429A) polymorphisms.


RESULTS
Variant allele carriers of the NQO1 (P187S) polymorphism showed a higher risk for high-stage disease than non-carriers at diagnosis [relative risk (RR)=1.4; 95% CI 1.0-1.8). A higher risk for highly malignant disease (T2+) was also observed in variant allele carriers than non-carriers of the GSTP1 (I105V) polymorphism (RR=1.6; 95% CI 1.1-2.5). NQO1 (R139W) variant allele carrier patients with intermediate malignant disease (TaG3+T1) had shorter disease-free survival than non-carriers (p=0.05). In contrast, carriers of the variant allele for the MTHFR (A222V) polymorphism had significantly longer disease-free survival than non-carriers (p=0.02).


CONCLUSIONS
Our data are consistent with the notion that NQO1 polymorphisms influence the course and clinical outcomes of urinary bladder neoplasms. However, our results need to be confirmed in a large study as most of the associations detected were only of marginal statistical significance, and would be lost on correction for multiple comparisons.
Sanyal
Somali
S
Division of Clinical Cancer Epidemiology, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
Ryk
Charlotta
C
De Verdier
Petra J
PJ
Steineck
Gunnar
G
Larsson
Per
P
Onelöv
Erik
E
Hemminki
Kari
K
Kumar
Rajiv
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi