P53 polymorphism in codon 72 and risk of human papillomavirus-induced cervical cancer: effect of inter-laboratory variation.
An association between codon-72 p53 polymorphism and risk of human papillomavirus (HPV)-induced cervical cancer has been found recently, but it has been difficult to replicate. In this study, we assess the impact of inter-laboratory variation in p53 genotyping on the validity of the proposed association. DNA specimens were randomly selected from 54 invasive, squamous cell carcinoma cases, 52 HPV-negative, and 39 HPV-positive controls from a previous case-control study in Brazil. Codon-72 polymorphism was blindly analyzed in three different laboratories. We calculated age- and race-adjusted odds ratios (OR) and 95% confidence intervals (CI) using logistic regression for gauging the association between p53 polymorphism and cervical cancer risk. The proportions of the Arg/Arg, Arg/Pro, and Pro/Pro genotypes varied substantially among laboratories with Kappa coefficients in the 0.49-0.63 range. When disagreement between labs was allowed, the OR for the Arg/Arg genotype, compared to other forms, was as low as 1.5 (95% CI: 0.5-3. 9). In contrast, the OR increased to 8.0 (95% CI: 2.3-28.5) after exclusion of discordant genotypes. Restricting the comparison to HPV-positive controls increased the magnitude of the relation appreciably. After exclusion of all discordant diagnoses, the OR was 21.5 (95% CI: 3.4-137.8), whereas with disagreed genotypes the association was not significant (OR = 2.9, 95% CI: 0.7-11.9). Homozygous codon-72 p53-Arg apparently confers a higher susceptibility to HPV-associated cervical tumorigenesis. However, exposure misclassification consequent to inter-laboratory variation in protocols may affect the ability to detect the association.
Makni
H
H
Department of Oncology, McGill University, Montreal, Canada.
Franco
E L
EL
Kaiano
J
J
Villa
L L
LL
Labrecque
S
S
Dudley
R
R
Storey
A
A
Matlashewski
G
G
D000328:Adult; D000368:Aged; D001120:Arginine / Q000235:genetics; D016022:Case-Control Studies; D003043:Cocarcinogenesis; D003062:Codon / Q000235:genetics*; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D015588:Observer Variation; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014412:Tumor Virus Infections / Q000150:complications / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology
D003062:Codon; D016159:Tumor Suppressor Protein p53; D001120:Arginine