Single nucleotide polymorphisms in antigen processing machinery component ERAPI significantly associate with clinical outcome in cervical carcinoma

Genetic variation of the antigen processing machinery (APM) components TAP2, LMP7, and ERAPI is related to cervical carcinoma risk, although the relation with expression and clinical outcome remains unknown. We have investigated the ccurrence of APM component single nucleotide polymorphisms (SNPs) in cervical carcinoma. Twelve nonsynonymous, coding SNPs in the TAPI, TAP2, LMP2, LMP7, and ERAPI genes were genotyped in 75 cervical carcinoma patients with known APM component and HLA class I expression levels. Individual genotype distributions were assessed for association with APM component expression, various histopathological parameters and survival. Genotype distributions at the ERAPI -56 and ERAPI-127 loci were significantly associated with overall survival (OS); haplotype construction spanning these two SNPs revealed that the combination of a major allele at ERAPI-56 and a minor allele at ERAPI-127 was significantly associated with survival, homozygosity for this haplotype being associated with decreased OS (5-year survival 50% vs. 70 and 81% for complete absence or heterozygosity for this haplotype, respectively; P - 0.021). Heterozygosity for this haplotype was an independent predictor for better OS in multivariate analysis (HR - 0.219; P - 0.014). These data indicate that genetic variation in APM component genes, particularly ERAPI, is an important contributing factor in cervical carcinogenesis, progressive tumor growth and survival. The location of the ERAPI-127 SNP in the peptidase M1 domain of the ERAP1 aminopeptidase suggests the possibility of direct functional consequences of variation at this locus.