Genetic Variants in TAP Are Associated with High-Grade Cervical Neoplasia

• Published in: Clinical cancer research Vol. 15; no. 3; pp. 1019 - 1023
• Main Authors: EINSTEIN, Mark H, LEANZA, Suzanne, CHIU, Lydia G, SCHLECHT, Nicolas F, GOLDBERG, Gary L, STEINBERG, Bettie M, BURK, Robert D
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2009
• Subjects: Antineoplastic agents; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; Cervical Intraepithelial Neoplasia - genetics; Cervical Intraepithelial Neoplasia - virology; CIN; Female; Female genital diseases; genetic polymorphisms; genetic susceptibility; Gynecology. Andrology. Obstetrics; human papillomavirus; Human papillomavirus 16; Humans; Medical sciences; Papillomavirus Infections - complications; Papillomavirus Infections - genetics; Pharmacology. Drug treatments; Polymorphism, Genetic; Risk Factors; TAP; Tumors; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - virology; Premalignant lesion; Genetic variant; Cervical intraepithelial neoplasia; Uterine cervix; Uterine cervix diseases; Female genital diseases; High grade; High malignancy
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-1207

Purpose: The transporter associated with antigen processing (TAP) is essential in assembling MHC-I proteins. Human papillomavirus (HPV) evades immune recognition by decreasing class I MHC cell surface expression through down-regulation of TAP1 levels. Consistent with heterogeneity in MHC expression is the individual variability in clearing detectable HPV infections. Genetic polymorphisms in TAP genes may affect protein structure, function, and the ability to clear HPV infection. Experimental Design: Case-control study of women with cervical intraepithelial neoplasia (CIN) II or III ( n = 114) and women without high-grade CIN ( n = 366). Five nonsynonymous single nucleotide polymorphisms (SNP) in TAP1 and TAP2 were genotyped using DNA collected in cervicovaginal lavage samples using microsphere array technology (Luminex xMAP). HPV typing was done using a PCR-based system with MY09/MY11 primers. TAP1 and TAP2 SNPs were validated by direct sequencing. Results: Differences in allele distribution between women with high-grade cervical neoplasia and women without was seen for TAP1 I333V ( P = 0.02) and TAP1 D637G ( P = 0.01). The odds ratios (OR) for CIN III were significantly lower among carriers of the TAP1 I333V polymorphism (OR, 0.28; 95% confidence interval, 0.1-0.8), and TAP1 D637G polymorphism (OR, 0.27; 95% confidence interval, 0.1-0.7). These associations remained significant even after restricting the evaluation to women who were positive for high-risk HPV types. Conclusions: In addition to the down-regulation of MHC-1 by oncogenic HPV, HPV pathogenesis might be facilitated by polymorphisms in the TAP proteins. Identifying TAP polymorphisms may potentially be used to identify women less susceptible to progression to high-grade CIN and cervical cancer.