title: XRCC1 codon 399 mutant allele: a risk factor for recurrence of urothelial bladder carcinoma in patients on BCG immunotherapy.
abstract: 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 = 12/60 months; 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.
authors: Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. ramamittal@yahoo.com
authors: Rama Devi
authors: RD
authors: Mittal
authors: Ranjana
authors: R
authors: Singh
authors: Parmeet Kaur
authors: PK
authors: Manchanda
authors: Dinesh
authors: D
authors: Ahirwar
authors: Ruchika
authors: R
authors: Gangwar
authors: Pravin
authors: P
authors: Kesarwani
authors: Anil
authors: A
authors: Mandhani
mesh_terms: D000368:Aged; D000483:Alleles; D001500:BCG Vaccine / Q000737:chemistry; D003062:Codon; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012306:Risk; D012307:Risk Factors; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D019459:Urothelium / Q000378:metabolism*; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D001500:BCG Vaccine; D003062:Codon; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human