The role of genetic factors involved in the development of undifferentiated nasopharyngeal carcinoma (UNPC) in nonendemic areas has been poorly investigated. High-resolution human leukocyte antigen (HLA) class I genotyping carried out in 82 Italian UNPC patients and 286 bone marrow donors born in the same province showed that A*0201, B*1801, and B*3501, known to efficiently present Epstein-Barr virus (EBV)-derived epitopes, were significantly under-represented in UNPC patients. Moreover, the A*0201/B*1801 haplotype was significantly less frequent in UNPC cases, with a 90% reduced risk (odds ratio [OR] 0.1, 95% confidence interval [CI] = 0.0-0.5) to develop UNPC, suggesting an additive effect. Notably, all 5 BARF1 epitopes and 7 of the 8 LMP-2 epitopes known to bind A*0201 showed a fully conserved sequence in all the 31 Italian EBV isolates investigated. The 4 amino acid changes affecting the 436-447 LMP-2 epitope do not reduce, but rather increase in two cases, the predicted ability of "variant" epitopes to bind the HLA-A*0201 allele, as shown by immunoinformatic analysis. Moreover, a significantly increased risk for UNPC was associated with A*2601 (OR 2.4, 95% CI = 1.1-4.9) and B*4101 (OR 9.2, 95% CI = 2.5-34.3). These findings indicate that Italian UNPC patients have a distinct HLA-A and -B genotypic profile and suggest that the decreased risk for UNPC conferred by definite HLA class I molecules is probably related to their ability to efficiently present LMP-2 and BARF1 epitopes that are highly conserved in EBV isolates from this geographic region. These results have practical implications for the immunotherapy of UNPC.
2009 UICC