Pathogenic variants in Steroid 5 alpha reductase type 3 (SRD5A3) cause rare inherited congenital disorder of glycosylation known as SRD5A3‐CDG (MIM# 612379). To date, 43 affected individuals have ...been reported. Despite the development of various dysmorphic features in significant number of patients, facial recognition entity has not yet been established for SRD5A3‐CDG. Herein, we reported a novel SRD5A3 missense pathogenic variant c.460 T > C p.(Ser154Pro). The 3D structural modeling of the SRD5A3 protein revealed additional transmembrane α‐helices and predicted that the p.(Ser154Pro) variant is located in a potential active site and is capable of reducing its catalytic efficiency. Based on phenotypes of our patients and all published SRD5A3‐CDG cases, we identified the most common clinical features as well as some recurrent dysmorphic features such as arched eyebrows, wide eyes, shallow nasal bridge, short nose, and large mouth. Based on facial digital 2D images, we successfully designed and validated a SRD5A3‐CDG computer based dysmorphic facial analysis, which achieved 92.5% accuracy. The current work integrates genotypic, 3D structural modeling and phenotypic characteristics of CDG‐SRD5A3 cases with the successful development of computer tool for accurate facial recognition of CDG‐SRD5A3 complex cases to assist in the diagnosis of this particular disorder globally.
DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve ...interpretation of missense variants, which remains a major challenge in human genetics.
We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature.
This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice.
Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene.
Objectives
Human leukocyte antigen‐G (HLA‐G) is implicated in several cancers and is considered to be an immune checkpoint regulator. We determined the association between polymorphisms in the ...3′ untranslated region of HLA‐G and soluble HLA‐G (sHLA‐G) expression with gynecological cancers (GCs).
Methods
A meta‐analysis was conducted to examine the association between HLA‐G14‐bp insertion (I)/deletion (D) and +3142C/G polymorphism in GC and to evaluate sHLA‐G expression
Results
We revealed a significant association between the +3142C/G polymorphism and invasive cervical cancer (ICC) based on the allelic model G versus C (odds ratio OR = 0.738, 95% confidence interval CI = 0.563–0.966, p = 0.027), dominant GG+GC versus CC (OR = 0.584, 95% CI = 0.395–0.862, p = 0.007), and codominant GG versus CC (OR = 0.527, 95% CI = 0.312–0.891, p = 0.017) models, suggesting that the G allele and GG genotype are protective against ICC. In gynecological precancerous patients with human papillomavirus (HPV) infection, we found that the 14‐bp I/D under the codominant DD versus DI model (OR = 0.492, 95% CI = 0.241–1.004, p = 0.051) was of borderline significance. Soluble HLA‐G levels were significantly higher in patients compared with healthy controls (standardized mean differences SMD = 1.434, 95% CI = 0.442–2.526, p = 0.005). Stratification by cancer type revealed that the sHLA‐G levels were significantly increased in cervical cancer (SMD = 4.889, 95% CI = 0.468–9.310, p = 0.030) and in subjects of Asian ethnicity (SMD = 4.889, 95% CI = 0.467–9.309, p = 0.030).
Conclusions
HLA‐G14‐bp I/D and +3142 C/G polymorphisms are associated with GC and HPV‐associated cervical cancer. In addition, we found significantly increased sHLA‐G levels in cancer patients. These results provide a basis for further studies in diagnostics and immunotherapy of GC.
Human leukocyte antigen‐G (HLA‐G)14‐bp insertion (I)/deletion (D) and+3142 C/G polymorphisms are associated with gynecological cancer (GC) and human papillomavirus‐associated cervical cancer. Soluble HLA‐G is significantly increased in GC.
HLA‐G is a non‐classical major histocompatibility complex class Ib molecule. Its expression has been described in various cancer types, including ovarian cancer. HLA‐G molecule has been implicated in ...immune escape and in progression of ovarian tumor cells. Our goal was to assess if total soluble (s)HLA‐G molecules or HLA‐G5 and sHLA‐G1 isoforms could be considered as circulating ovarian tumor biomarkers, we measured the concentration of these molecules in ovarian carcinoma patients stratified according with their clinicopathological parameters. sHLA‐G, sHLA‐G1 and HLA‐G5 concentrations were dosed in plasma samples by sandwich‐ELISA. The sHLA‐G dimerization was analyzed after immunoprecipitation and SDS‐PAGE migration. Total sHLA‐G and sHLA‐G1 levels were significantly represented in plasma of ovarian carcinoma patients compared to healthy controls. sHLA‐G1 isoform concentration was highly represented in ovarian carcinoma compared to HLA‐G5 isoforms. Additionally, high sHLA‐G molecules have been found in aged patients, as well as in patients with advanced stages, and those with metastatic lymph nodes and those with distant metastasis. Elsewhere, sHLA‐G monomers were highly represented in ovarian carcinoma patients compared to controls. sHLA‐G plasmatic protein was highly represented in ovarian carcinoma. In effect, HLA‐G might be considered as a new checkpoint molecule that could be used to assess progression and recurrence of the disease, thus placing it as a potential biomarker for advanced and complicated ovarian carcinoma.
Conflicting results on the association between HLA-G and digestive cancers were reported. We conducted a meta-analysis to further investigate the true relationship between HLA-G and digestive cancers ...(DC).
Following PRISMA guidelines, we performed a meta-analysis including 7 case-control studies on HLA-G 14-bp Insertion/deletion (I/D) polymorphism, and 15 studies on soluble HLA-G (sHLA-G). Odds ratios (OR) and their corresponding 95% confidence intervals (CI) for genetic polymorphisms were calculated. The pooled OR was calculated under three genetic models: allelic, recessive, and dominant models. Concerning sHLA-G meta-analysis, standardized mean differences (SMDs) were calculated.
The HLA-G 14-bp I/D was not associated with the risk of DC. However, in the subset of HBV/HCV positive hepato-cellular cancer (HCC) patients, we reported a significant association of HLA-G 14-bp I/D with the disease initiation under allelic (D vs. I; OR = 1.698, 95% CI = 1.263–2.282, p = 0.000), dominant (DD + ID vs. II; OR = 2.321, 95% CI = 1.277–4.218, p = 0.006)and recessive (DD vs. DI + II; OR = 1.739, 95% CI = 1.173–2.577, p = 0.006) genetic models. Interestingly, HLA-G 14-bp I/D was not associated with the disease initiation in HBV/HCV negative HCC patients. However, the infection by HBV/HCV seems to be implicated in the HCC development when we compared HBV/HCV positive patients to HBV/HCV negative patients under allelic (D vs. I; OR = 1.429, 95% CI = 1.029–1.983, p = 0.033, and dominant (DD + ID vs.II; OR = 1.981, 95% CI = 1.002–3.916, p = 0.049) genetic models.
Overall analysis of DC showed significant increased sHLA-G in patients compared to healthy controls (SMD = 3.341, 95% CI = 2.415–4.267, p = 0.000). In Asian patients with gastric cancer, sHLA-G was significantly increased in grade 3 compared to low grades (SMD = 0.448, 95% CI = 0.109–0.787, p = 0.000). Further analysis showed that sHLA-G was significantly increased in positive DC vascular invasion (SMD = 0.743, 95% CI = 0.385–1.100, p = 0.000). Accordingly, sHLA-G was associated with a poor prognosis for DC.
The current meta-analysis supports the significant role of HLA-G in DC. The HLA-G 14-bp I/D polymorphism was associated with HCC patients with concomitant HBV/HCV viral infections. Increased sHLA-G indicated a poor prognosis for DC cancer patients.
Digestive cancer; HLA-G; Polymorphism; sHLA-G; Meta-analysis.
•Significant association of HLA-G 14-bp Ins/Del with breast cancer susceptibility.•High protective role of the HLA-G +3142 C/G polymorphism against breast cancer.•Significant high sHLA-G levels in ...patients with breast cancer.•A critical role of HLA-G in breast cancer.•HLA-G as a new theranostic biomarker.
Human leukocyte antigen-G (HLA-G) gene polymorphisms and circulating sHLA-G have often been linked to the risk of breast cancer (BC). However, the results remain controversial. To resolve this issue, we performed a meta-analysis of HLA-G gene polymorphisms and sHLA-G levels in BC.
We performed a meta-analysis on the association of HLA-G 14-bp Insertion/Deletion (Ins/Del) and HLA-G +3142 C/G polymorphisms with BC as well as the relationship between sHLA-G and the disease outcome.
Pooled analysis showed a statistically significant association between the HLA-G 14-bp Ins/Del polymorphism and BC susceptibility for the overall population and for Caucasians. The Del allele and genotypes with at least one copy of the Del allele presented significant risks for BC. For HLA-G +3142 C/G polymorphism, the G allele significantly decreased the risk of BC for the overall population and for Caucasians, indicating that the G allele was a protective factor against BC and that the C allele was a significant risk factor for BC. The meta-analysis revealed a significantly increased level of sHLA-G patients with BC compared to the control group for the overall population, Caucasians and Asians.
The present meta-analysis showed a major association of both HLA-G 14-bp Ins/Del and +3142 C/G polymorphisms with BC susceptibility, suggesting Del and C variants as highly significant risk factors for BC. The present study also showed significantly higher sHLA-G levels in patients with BC compared to healthy controls. Our pooled results suggested a critical role of HLA-G in BC, thereby providing evidence to use HLA-G as a biomarker and a therapeutic tool.
Little is known about non‐classical HLA molecules in vulvar squamous cell carcinoma (VSCC). Because of the indoleamine‐2,3‐dioxygenase (IDO) immune tolerant role in association with HLA‐G, we ...evaluated the clinical and prognostic value of HLA‐G, HLA‐E, and IDO in VSCC. HLA‐G, HLA‐E, and IDO expression was determined by immunohistochemistry in VSCC and associated with clinicopathological parameters and disease outcome. These three molecules were highly represented in tumoral tissues vs healthy matched vulvar tissues (P = 0.0001). Significant differences in HLA‐G expression in stages, tumor size, tumor invasion depth, and resection margins subgroups were reported (P < 0.05). At 5 years, the cumulative survival rates was of 79.8% in patients with HLA‐Glow expression vs 12.5% in those with HLA‐Ghigh expression (P < 3 × 10−5). Similarly, patients with IDOhigh expression were at a significantly reduced overall survival (OS) and disease‐free survival (DFS) rates (P = 0.011 and 0.045, respectively). The overexpression of the three molecules together worsen survival rates of VSCC patients (OS: P = 0.000038, DFS: P = 0.000085). Altogether, our results showed that HLA‐G, HLA‐E, and IDO may represent novel candidate markers for patients' prognosis and potential targets for VSCC therapy.
sHLA-G as a biomarker for colorectal cancer pathogenesis Dhouioui, Sabrine; Boujelbene, Nadia; Chelbi, Hanen ...
Journal of King Saud University. Science,
January 2022, 2022-01-00, 2022-01-01, Volume:
34, Issue:
1
Journal Article
Peer reviewed
Open access
Colorectal cancer (CRC) is a serious gastrointestinal disease. Cancer cells can survive in a microenvironment that includes distinct immune cells, various immune checkpoints including HLA-G, and ...different immune effectors such as interleukin-6 (IL-6), TNF-alpha (TNF-α), and interferon-gamma (IFN-γ). Thus, the objective of this study was to investigate HLA-G involvement in CRC as a prognostic factor in the Tunisian population, both in its soluble form (sHLA-G) and in its form linked to extracellular vesicles (HLA-GEV). Additionally, we examined its association to the secretion of cytokines.
Fifty Tunisian patients, diagnosed with CRC, matched with ninety-eight healthy blood donors (HD) were enrolled in this study. Levels of sHLA-G, HLA-GEV, IL-6, TNF-α, and IFN-γ were dosed in plasma samples using specific ELISA. For the functional assay, we assessed sHLA-G effects on the production of cytokines by stimulated T lymphocytes. We measured the concentration of IL-6, TNF-α, and IFN-γ produced by activated T lymphocytes pre-stimulated by plasma sHLA-G and HLA-GEV.
Our case-control analysis showed high concentration of both sHLA-G (8.8 0–63 ng/ml vs. 2.1 0–63 ng/ml, p < 0.0001) and HLA-GEV (0.9 0–17.8 ng/ml vs. 0.3 0–31.0 ng/ml, p = 0.018) in CRC patients compared to HD. Concerning cytokines, IL-6 exclusively increased compared to HD (7.10.0–104.0 pg/ml vs. 3.60.0–58.22 pg/ml, p = 0.005). The evaluation of diagnostic performance using the receiver operating characteristic (ROC) curves and the area under the curve (AUC) showed sHLA-G (AUC = 0.828) as the more adequate biomarker in colorectal carcinoma prediction compared to HLA-GEV (AUC = 0.615) and IL-6 (AUC = 0.664). We found that sHLA-G is able to decrease IL-6, TNF-α, and IFN-γ production by stimulated T lymphocytes in a concentration-independent manner. Additionally, HLA-GEV appears to downregulate solely IL-6 release by stimulated T lymphocytes. Interestingly, HLA-GEV was related to lymph node infiltration, which represents the most common metastatic route for colorectal cancer via the lymphatic system.
We outlined the importance of sHLA-G and HLA-GEV as substantial immune biomarkers in CRC. Our findings suggest that HLA-G could be an effective diagnostic tool for colorectal cancer.
Human leukocyte antigen (HLA)-G has been considered as an immune modulator in several types of cancers. Its genetic polymorphisms may potentially affect the risk of developing colorectal cancer ...(CRC). The overall purpose of this study was to analyze the implication of HLA-G 3′untranslated region (3′UTR) polymorphisms particularly 14 pb insertion/deletion (Ins/Del; rs371194629) and + 3142C/G (rs1063320) in CRC susceptibility and progression.
A comparative analysis between patients (N = 233) and controls (N = 241) demonstrated that Del allele (Odds Ratios (OR) = 1.41, 95% CI = 1.091–1.819, p = 0.008), the homozygous Del/Del genotype (OR = 1.80, 95% CI = 1.205–2.664, p = 0.003) and the codominant C/G genotype (OR = 1.59, 95% CI = 1.106–2.272, p = 0.013) were associated to CRC risk. As expected, the DelG haplotype was associated with CRC susceptibility (OR = 1.47, 95% CI = 1.068–2.012, p = 0.018). Assessment of patients' survival by Kaplan-Meier analysis indicated that the Del allele and the homozygous Del/Del genotype were associated with reduced event free survival (EFS) (Respectively, p = 0.009 and p = 0.05). Interestingly, the Del allele and the homozygous Del/Del genotype have been revealed as independent prognostic factors for poor EFS in patients with CRC. Additionally, haplotypes analysis revealed that DelG haplotype was linked with significant increase in CRC risk (log-rank; EFS: p = 0.02). Inversely, the InsC haplotype was associated with a significant reduced CRC risk (log-rank; Overall survival (OS): p < 10–6; EFS: p = 0.01). Multivariate Cox regression analysis revealed that the InsC haplotype was independently associated with significantly longer EFS (p = 0.021, HR = 0.636, 95% CI = 0.433–0.935).
These findings support the implication of HLA-G polymorphisms in the CRC susceptibility suggesting HLA-G as a potent prognostic and predictive indicator for CRC. Insight into mechanisms underlying HLA-G polymorphisms could allow for the development of targeted care for CRC patients according to their genetic profile.
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