Abstract
Expression of the non-classical human leukocyte antigen-G (HLA-G) promotes cancer progression in various malignancies including epithelial ovarian cancer (EOC). As single nucleotide polymorphisms (SNPs) in the HLA-G 3′ untranslated region (UTR) regulate HLA-G expression, we investigated HLA-G 3′UTR haplotypes arranged by SNPs in healthy controls (n = 75) and primary EOC patients (n = 79) and determined soluble HLA-G (sHLA-G) levels. Results were related to the clinical status and outcome. Although haplotype frequencies were similar in patients and controls, (i) sHLA-G levels were increased in EOC independent of the haplotype, (ii) homozygosity for UTR-1 or UTR-2 genotypes were significantly associated with metastases formation and presence of circulating tumor cells before therapy, whereas (iii) the UTR-5 and UTR-7 haplotypes were significantly associated with a beneficial clinical outcome regarding negative nodal status, early FIGO staging, and improved overall survival. Lastly, (iv) the ambivalent impact on clinical EOC aspects could be deduced to specific SNPs in the HLA-G 3′UTR: +3187G, +3196G and +3035T alleles. Our results give evidence that even if the genetic background of the HLA-G 3′UTR is identical between patients and controls, certain SNPs have the potential to contribute to diametrical clinical status/outcome in EOC.
Highlights
The human leukocyte antigen G (HLA-G), a non-classical human leukocyte antigen, belongs to the immune checkpoint molecules that regulate/control immune effector responses
We demonstrate for the first time (i) that haplotype frequencies of the human leukocyte antigen-G (HLA-G) 3′untranslated region (UTR) between healthy controls and epithelial ovarian cancer (EOC) patients are comparable soluble HLA-G (sHLA-G) levels of patients were significantly increased compared to healthy donors (HD) independent of their HLA-G 3′UTR haplotype, (ii) that homozygosity for UTR-1 or UTR-2 genotypes are significantly associated with metastases formation and presence of circulating tumor cells (CTCs) before therapy, (iii) that the UTR-5 and UTR-7 haplotypes are associated with a beneficial clinical outcome, with regards to negative nodal status, early Federation of Gynecology and Obstetrics (FIGO) staging and improved overall patient survival (OS), and lastly (iv) that certain allelic variants, among which +3187G, +3196G and +3035T in the HLA-G 3′UTR have ambivalent impact on clinical aspects of EOC
We propose that even if the genetic background of the HLA-G 3′UTR is identical between physiologic and pathologic conditions, presence of certain single nucleotide polymorphisms (SNP) within important regulatory sequences in the HLA-G 3′UTR have the potential to contribute to an adverse or beneficial clinical status in EOC
Summary
The human leukocyte antigen G (HLA-G), a non-classical human leukocyte antigen, belongs to the immune checkpoint molecules that regulate/control immune effector responses. The regulation of HLA-G expression and of its soluble forms encompasses post-transcriptional processes among which alternative splicing, altered mRNA stability, microRNA-mediated protein expression and impaired protein transport to the cell surface[2]. In analogy with other clinical disorders[30,31], variable HLA-G 3′UTR sites in combination with the cellular microenvironment may be critical in influencing HLA-G expression In this retrospective study we (i) defined the HLA-G 3′UTR haplotypes from primary patients with serous ovarian carcinoma, (ii) determined the association of the genetic background with the presence of CTCs, and (iii) analyzed the impact of the genetic background on clinical status and disease outcome of EOC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
