XRCC1 codon 399 mutant allele: A risk factor for recurrence of urothelial bladder carcinoma in patients on BCG immunotherapy

Rama Devi Mittal, Ranjana Singh, Parmeet Kaur Manchanda, Dinesh Ahirwar, Ruchika Gangwar, Pravin Kesarwani and Anil Mandhani

volume 7 | issue 5

May 2008
Pages: 645 - 650

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XRCC1 protein plays crucial role in base excision repair (BER) by acting as a scaffold for other BER enzymes. Variants in XRCC1 gene might alter protein structure/function or create alternatively spliced protein influencing BER efficiency and affect individual susceptibility/recurrence to urinary bladder cancer (BC). We tested whether polymorphisms in XRCC1 gene were associated with BC risk and further to substantiate risk of recurrence after Bacillus Calmette-Guerin (BCG) immunotherapy. Genotyping for three polymorphic sites of XRCC1 gene at codon Arg194Trp (PvuII), Arg280His (RsaI) and, Arg399Gln (MspI) in 140 BC cases and 190 controls by PCR-RFLP method was done. We observed significant association in heterozygous genotype (GA) of codon 280 and 399 with BC risk (OR=1.96, p=0.021 and OR = 1.81, p=0.021, respectively), however no association was seen for variant AA genotype. A trend of increased risk with high stage and grade in patients with codon 194 variant genotypes (CT+TT) was observed. Haplotype analysis showed that individuals with haplotype 194C-280G-399A were at >3-fold higher risk for BC (OR=3.48, p=0.01). The A/A genotype of codon 399 was associated with high risk for recurrence in BCG treated patients (HR=5.05, P=0.01) thus, showing reduced recurrence free survival (AA/GG=12/60months; log rank P=0.004). The study suggested no association of variant genotypes with the susceptibility to BC. Haplotype analysis however, revealed that XRCC1 399 A allele may have a major role as patients with haplotype 194C-280G-399A carrying variant allele of 399 were at higher risk. Running Title XRCC1 gene polymorphism and risk of recurrence after BCG immunotherapy