Background:The identification in breast cancer (BC) of novel genetic
biomarkers regulating natural killer (NK) cell function, including the HLA, KIR, and
CD16A (FCGR3A), may be still a challenge.Objective:We aimed to evaluate whether the combined effect of these polymorphisms
has an impact on BC susceptibility and progression.Methods:47 BC Italian patients and healthy individuals (39 females and 66 males/
females) were genotyped by Sanger sequencing (HLA-C exon 2-4 and FCGR3A-
158V/F, 48L/R/H) and PCR-SSP typing (KIR genes).Results:HLA-C gene allele analysis showed the group C1, with HLA-C*07:02:01 allele,
to be significantly associated with tumor progression (16.7% vs. 4.0%, p=0.04,
OR=4.867), and instead, group C2, with HLA-C*05:01:01, was protective against
disease susceptibility (0.0% vs. 7.2%, p=0.019, OR=0.087). In addition, we highlighted a
significant reduction of the KIR2DS4ins in BC patients (pcorr.=0.022) and an increased
combined presence of KIR2DL1 and KIR2DS1 genes in advanced BC patients
compared to earlier stages (66.7% vs. 19.2%, p=0.002). The concurrent lack of
KIR2DL2 and KIR2DS4 genes in the presence of HLA-C2 alleles was significantly
associated with increased susceptibility to BC (p=0.012, OR=5.020) or with lymph node
involvement (p=0.008, OR=6.375). Lastly, we identified different combinations of the
FCGR3A-48/158 variants and KIR genes in BC patients compared to controls.Conclusion:Our findings suggest that in the development of BC probably exists a
disorder of the NK innate immunity influenced by KIR/HLA-C gene content and
FCGR3A-158 polymorphisms and that the combined analysis of these biomarkers might
help predict genetic risk scores for tailored screening of BC patients in therapy.