Identification of HLA-DQα and -DRβ Residues Associated With Susceptibility and Protection to Epithelial Ovarian Cancer

Abstract

Substantial evidence has been accumulated suggesting that T cells in patients with epithelial ovarian carcinoma (EOC) exhibit an antigen-driven immune response directed against the tumor cells. In the context of human leukocyte antigen (HLA), this suggests its possible involvement in the disease. Therefore, we examined the distribution of the HLA-DRB1*, -DQA1*, and -DQB1* alleles in 47 patients with EOC and 67 healthy Caucasian women. The frequency of D 70 and E 71 polymorphic residues of the DRB1 alleles was significantly reduced in EOC patients versus controls ( pD 70E 71 = 0.009), suggesting a protective role against the disease. The DQα residues R 52 and Y 11R 55 were increased in the patients ( p = 0.008 and 0.012, respectively). Because residues 11 and 55 participate in the formation of pocket 1, they may be functionally important amino acid positions that influence disease susceptibility. The frequency of the DQα susceptibility epitope (R 52Y 11R 55) among the DRβD 70E 71-positive EOC patients was increased when compared with DRβD 70E 71-positive controls (EOC, 100%; control, 52%; p = 0.028). Among individuals without the DQα susceptibility epitope, the distribution of DRβD 70E 71-positive cases was significantly different between EOC patients and controls (EOC, 0%; control, 60%; p = 0.039). Therefore, it appears that the presence of DQα susceptibility elements overrides the protective effect of the DRβD 70E 71 epitope and suggests an interactive relationship between DRβ and DQα epitopes that may be of importance for disease susceptibility. Because positions DRβ 70,71 and DQα 52 have been implicated in immunologic diseases, it is likely that besides being critical for T-cell recognition, they may also play a role in T-cell development and acquisition of the T-cell repertoire.