The analysis of genetic data regarding HLA, KIR and CD16A gene contents may be challenging to understand their influence on the function of NK cells in modulating immune response in the breast cancer (BC). We investigated the combined effect of the KIR genes and their HLA-C ligands together with CD16A on development and progression to disease in 47 Italian patients (pts) and two groups of control (Ctrs, 39 females and 66 males/females). The gene polymorphisms were investigated by PCR-SSP typing (KIR) and PCR-SBT method (HLA-C and FCGR3A). HLA-C results showed a predisposing effect of the HLA-C*07:02:01 allele to malignancy (III-IV grade: 16.7% vs 3.9% p=0.019 OR=4.867), while the HLA-C*05:01:01 allele in BC patients resulted protective towards BC onset when compared with mixed Ctrs (0% vs 7.24%, p=0.0187 OR=0.0873). This finding could be explained by a known different expression of these two antigens due to structure of the peptide-binding cleft that could modify efficacy of the immune response towards cancer. Analyzing single KIR genes, we evidenced a higher frequency of KIR2DS1 gene in more aggressive neoplasms (III-IV stage 63.2% vs 0-II 32.1%, p=0.043) and on the contrary a protective role of the KIR2DL2 and KIR2DS4ins genes, linked on the same haplotype. Particularly, KIR2DL2 was significantly less frequent in these aggressive BC pts when its ligand was missing (KIR2DL2 HLA-C2: 20.0% vs 57.9%, p=0.016). The synergic absence of these two KIR genes increased the occurrence of more advanced BC by 5.7-fold (63.2% vs 23.1% in Ctrs p=0.0071) and even more strongly in presence of HLA-C2 ligand (60.0% vs 10.5%, p=0.0005 OR=12.75). This type of KIR/HLA genetic association recalled the model of immune activation in psoriatic arthritis. Regarding FCGR3 AA48 A/T/G and 158 G/T gene polymorphisms, we described a higher frequency of 48T-158G haplotype in BC pts (44.2% vs 37.5% in FCtr) and an increased incidence of 48LL-FV,158VV haplotype in relapsing BC (90% vs 55%).
INFLUENCE OF HLA-KIR AND FCGR3A GENES ON BREAST CANCER DEVELOPMENT AND PROGRESSION
Aureli Anna;Canossi Angelica;Del Beato Tiziana;Sconocchia Giuseppe
2019
Abstract
The analysis of genetic data regarding HLA, KIR and CD16A gene contents may be challenging to understand their influence on the function of NK cells in modulating immune response in the breast cancer (BC). We investigated the combined effect of the KIR genes and their HLA-C ligands together with CD16A on development and progression to disease in 47 Italian patients (pts) and two groups of control (Ctrs, 39 females and 66 males/females). The gene polymorphisms were investigated by PCR-SSP typing (KIR) and PCR-SBT method (HLA-C and FCGR3A). HLA-C results showed a predisposing effect of the HLA-C*07:02:01 allele to malignancy (III-IV grade: 16.7% vs 3.9% p=0.019 OR=4.867), while the HLA-C*05:01:01 allele in BC patients resulted protective towards BC onset when compared with mixed Ctrs (0% vs 7.24%, p=0.0187 OR=0.0873). This finding could be explained by a known different expression of these two antigens due to structure of the peptide-binding cleft that could modify efficacy of the immune response towards cancer. Analyzing single KIR genes, we evidenced a higher frequency of KIR2DS1 gene in more aggressive neoplasms (III-IV stage 63.2% vs 0-II 32.1%, p=0.043) and on the contrary a protective role of the KIR2DL2 and KIR2DS4ins genes, linked on the same haplotype. Particularly, KIR2DL2 was significantly less frequent in these aggressive BC pts when its ligand was missing (KIR2DL2 HLA-C2: 20.0% vs 57.9%, p=0.016). The synergic absence of these two KIR genes increased the occurrence of more advanced BC by 5.7-fold (63.2% vs 23.1% in Ctrs p=0.0071) and even more strongly in presence of HLA-C2 ligand (60.0% vs 10.5%, p=0.0005 OR=12.75). This type of KIR/HLA genetic association recalled the model of immune activation in psoriatic arthritis. Regarding FCGR3 AA48 A/T/G and 158 G/T gene polymorphisms, we described a higher frequency of 48T-158G haplotype in BC pts (44.2% vs 37.5% in FCtr) and an increased incidence of 48LL-FV,158VV haplotype in relapsing BC (90% vs 55%).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
