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Human leukocyte antigen (HLA)-G is an immune checkpoint molecule that is highly expressed in papillary thyroid carcinoma (PTC). The <i>HLA-G</i> gene presents several functional polymorphisms distributed across the coding and regulatory regions (5′URR: 5′ upstream regulatory region and 3′UTR: 3′ untranslated region) and some of them may impact HLA-G expression and human malignancy. To understand the contribution of the <i>HLA-G</i> genetic background in PTC, we studied the <i>HLA-G</i> gene variability in PTC patients in association with tumor morbidity, HLA-G tissue expression, and plasma soluble (sHLA-G) levels. We evaluated 185 PTC patients and 154 healthy controls. Polymorphic sites defining coding, regulatory and extended haplotypes were characterized by sequencing analyses. HLA-G tissue expression and plasma soluble HLA-G levels were evaluated by immunohistochemistry and ELISA, respectively. Compared to the controls, the <i>G</i>0104a_(5′URR)<i>G*</i>01:04:04_(coding)UTR-03_(3’UTR) extended haplotype was underrepresented in the PTC patients, while <i>G</i>0104a_(5′URR)<i>G*</i>01:04:01_(coding)UTR-03_(3′UTR) was less frequent in patients with metastatic and multifocal tumors. Decreased HLA-G tissue expression and undetectable plasma sHLA-G were associated with the <i>G</i>010102a_(5′URR)<i>G*</i>01:01:02:01_(coding)UTR-02_(3′UTR) extended haplotype. We concluded that the <i>HLA-G</i> variability was associated with PTC development and morbidity, as well as the magnitude of the encoded protein expression at local and systemic levels.