Effect of genetic polymorphisms on urinary bladder neoplasms

Urinary bladder neoplasms (UBNs) are among the most common malignancies in the world and are mainly attributed to exogenous risk factors such as, smoking, exposure to industrial aromatic amines and certain medicinal drugs which cause DNA damage. The entire process leading to DNA damage and subsequent repair of the damage involves a plethora of enzymes including those involved in metabolic and DNA repair processes. Genetic polymorphisms in the genes encoding enzymes involved in these processes can potentially modulate susceptibility to cancer as well as alter the clinical course and treatment response in this disease. Despite previous studies, a comprehensive investigation on the role of polymorphisms in the genes involved in metabolism and DNA repair in UBNs has been lacking. The main objective of this thesis was to investigate the role of polymorphisms in DNA repair, metabolic and cell-cycle regulatory genes in the susceptibility, pathogenesis and clinical behavior of UBNs. The cases included bladder cancer patients, diagnosed during 1995-96 in different hospitals of the Stockholm County area. Follow-up information about the cases was recorded for 5 years. The controls were also drawn from the Swedish population. Both the cases and controls were genotyped for polymorphisms in different DNA repair, cell-cycle regulatory and metabolic genes. The results from the population based association studies (paper I & II) showed that the variant allele homozygotes of the A499V (C>T) and K939Q (A>C) polymorphisms in the XPC gene were associated with 6- and 3-fold increased risk of UBNs, respectively. Moreover, the variant allele genotypes of the A499V (C>T) polymorphism were associated with decreased age of disease onset. Increased risk of disease was also observed with the variant allele haplotypes of these two polymorphisms. Increasing number of XPC variant alleles (499V and 939Q) in the genotypes increased the risk of UBNs in a linear dose dependent manner. We also observed a 2.5 times higher risk of UBNs in the individuals lacking the GSTT1 gene than those who did not. In contrast, the variant allele homozygote genotype of H27H (T>C) polymorphism in the H-ras gene was associated with a decreased risk of UBNs. Our studies on the influence of polymorphisms on the disease course and clinical outcomes in UBNs (paper III & IV) showed that patients, who were simultaneous carriers of variant alleles for the K751Q (A>C) and K939Q (A>C) polymorphisms in the XPD and XPC genes, respectively had longer disease free survival than the rest of the patients. Longer disease free survival was also observed in the carriers than the non-carriers of variant allele for A222V (C>T) polymorphism in the MTHFR gene. In contrast, compared to the non-carriers, carriers of the variant allele for R139W (C>T) polymorphism in the NQO1 gene showed shorter disease free survival in T1 disease. The variant allele carriers of R399Q (G>A) polymorphism in the XRCC1 gene were at reduced risk for recurrence and death after instillation and radiotherapy. A significant low-risk for stage progression was observed in patients carrying the variant allele for H27H (T>C) polymorphism in the H-ras gene. The variant allele carriers of G39E (G>A), P187S (C>T) and I105V (A>G) polymorphisms in the MSH6, NQO1 and GSTP1 genes, respectively showed association with increased risk for highly malignant UBNs. In conclusion, our results are consistent with the notion that the DNA repair, cell-cycle regulatory and metabolic gene polymorphisms influence the susceptibility to UBNs as well as the disease course and outcomes in patients with this disease