title: Undifferentiated nasopharyngeal carcinoma from a nonendemic area: protective role of HLA allele products presenting conserved EBV epitopes.
abstract: 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.
authors.affiliation: Cancer Bioimmunotherapy Unit, IRCCS-National Cancer Institute, Aviano (PN), Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pasini
authors.forename: Laura
authors.initials: L
authors.lastname: Caggiari
authors.forename: Luigino
authors.initials: L
authors.lastname: Dal Maso
authors.forename: Debora
authors.initials: D
authors.lastname: Martorelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Guidoboni
authors.forename: Emanuela
authors.initials: E
authors.lastname: Vaccher
authors.forename: Luigi
authors.initials: L
authors.lastname: Barzan
authors.forename: Giovanni
authors.initials: G
authors.lastname: Franchin
authors.forename: Annunziata
authors.initials: A
authors.lastname: Gloghini
authors.forename: Valli
authors.initials: V
authors.lastname: De Re
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Sacchi
authors.forename: Diego
authors.initials: D
authors.lastname: Serraino
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002454:Cell Differentiation; D000939:Epitopes / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D005260:Female; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000821:virology; D014763:Viral Matrix Proteins / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*; D055815:Young Adult
chemical_list: C086495:BARF1 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D000939:Epitopes; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D014763:Viral Matrix Proteins; D014764:Viral Proteins