Pharmacogenomics & Personalized Medicine最新文献

Background: The incidence of cutaneous melanoma continues to rise rapidly and has an extremely poor prognosis. Immunotherapy strategies are the most effective approach for patients who have developed metastases, but not all cases have been successful due to the complex and variable mechanisms of melanoma response to immune checkpoint inhibition.

Methods: We synthesized collagen-coding gene expression data (second-generation and single-cell sequencing) from public Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatics analysis was performed using R software and several database resources such as Metascape database, Gene Set Cancer Analysis (GSCA) database, and Cytoscape software, etc., to investigate the biological mechanisms that may be related with collagens. Immunofluorescence and immunohistochemical staining were used to validate the expression and localization of Nidogen-2 (NID2).

Results: Melanoma patients can be divided into two collagen clusters. Patients with high collagen levels (C1) had a shorter survival than those with low collagen levels (C2) and were less likely to benefit from immunotherapy. We demonstrated that NID2 is a potential key factor in the collagen phenotype, is involved in fibroblast activation in melanoma, and forms a barrier to limit the proximity of CD8+ T cells to tumor cells.

Conclusion: We clarified the adverse effects of collagen on melanoma patients and identified NID2 as a potential therapeutic target.

The application of pharmacogenetics in oncology is part of the routine clinical practice. In particular, genotyping of dihydropyrimidine dehydrogenase (DPYD) and UDP-glucuronosyltransferase (UGT1A1) is crucial to manage the treatment of patients taking fluoropyrimidines and irinotecan. The unique approach of our laboratory to the pharmacogenetic diagnostic service in oncology is to combine two real-time PCR methods, LightSNiP assay (TIB MOLBIOL), and more recently FRET (Fluorescent Resonance Energy Transfer) probes technology (Nuclear Laser Medicine), plus TaqMan assay (Thermo Fisher) for the confirmation of the presence of variant alleles on DNA from a second extraction. We found that both the FRET and LightSNiP assays, where detection occurs by melting curve analysis, offer an advantage over the competing TaqMan technology. Whereas unexpected genetic variants may be missed using a mutation-specific TaqMan assay, the information thus obtained can be useful to adjust the therapy in case of unexpected post-treatment toxicity. The combination of TaqMan and FRET assays helped us to achieve more accurate genotyping and a correct result for the patient. The added value of the DPYD FRET assay is the possibility of detecting, with the same amplification profile of the polymorphisms detailed in the guidelines, also the c.2194G>A (*6 rs1801160), cited in the recommendations as a variant to be investigated in case of severe toxicity. Regarding the UGT1A1 (TA)n promoter polymorphism (rs3064744), the distinctive and positive feature of the FRET assay is to allow clearly identifying all those potential variant alleles, including the (TA)5 and (TA)8 alleles, that are frequent in African Americans. Our clinical practice emphasizes the importance of not only rapid and easy-to-use assays, such as the new FRET ones, but also of accurate and comprehensive genotyping for good pharmacogenetic diagnostic activity.

Background: We report the genetic etiology of a case of bilateral vocal cord paralysis in a female infant.

Case description: The female infant developed dyspnea after birth, which improved with treatment, allowing her to be discharged from the local hospital. At 2 months of age, the child experienced a recurrence of dyspnea and was treated in a local hospital with interventions such as tracheal intubation and mechanical ventilation. However, as the child continued to suffer from dyspnea, she was transferred to the neonatal intensive care unit of the Children's Hospital affiliated to Zhengzhou University for further treatment. A second electronic nasopharyngoscopy examination revealed bilateral vocal cord paralysis. The child underwent a tracheostomy due to a failure to wean from mechanical ventilation; after surgery, the respirator was effectively removed, and oxygen delivery ceased. The child and her parents underwent genetic testing with next-generation sequencing technology, which revealed that the child had two heterozygous variants in the MUSK gene, namely the c.2287G>A heterozygous mutation (p.Ala763Thr) and the c.790C>T heterozygous mutation. In addition, Sanger sequencing was performed, which confirmed that these two mutations were, respectively, inherited from the mother and father.

Conclusion: Congenital myasthenic syndrome caused by MUSK gene mutations can present clinically as bilateral vocal cord paralysis in neonates.

The clinical manifestations of Danon disease, which result from the primary deficiency of the lysosome-associated membrane protein 2 gene, include cardiomyopathy, skeletal myopathy, and different degrees of intellectual disability that vary greatly among patients. The present study reports on two cases of Danon disease in two patients who only presented cardiac symptoms. Cardiac symptoms usually occur in adolescence and during a patient's twenties, and most patients die from heart failure. However, the lab results from these cases suggested that other systems were involved, despite no other clinical symptoms. Significantly, the two patients had elevated serum cardiac troponin I, which often manifests in the acute cardiac phase, especially in severely affected patients with rapidly fatal outcomes. Danon disease is a multi-system involvement disease. Therefore, clinicians must be aware of its complexity when evaluating newly diagnosed patients due to its vastly different clinical course and prognosis and the importance of multidisciplinary management.

Background: GABRP has been reported to play an oncogenic role in various carcinomas. However, no report has been found for its involvement in lung squamous cell carcinoma (LUSC) development yet. We aimed to explore the expression and prognostic roles of GABRP and assessment of its association with tumor microenvironment in LUSC.

Methods: The GABRP expression in LUSC was analyzed using TCGA, GEO, and HPA databases. The Kaplan-Meier, Cox regression analysis, and receiver operating characteristic (ROC) curve were applied to assess the prognostic and diagnostic values of GABRP in LUSC. We also performed ESTIMATE and ssGSEA to explore the association between GABRP expression and immune cell infiltrations. GABRP was highly expressed in LUSC patients, and up-regulation of GABRP was associated with shorter overall survival (OS). Cox regression analysis indicated that GABRP was an independent prognostic factor for LUSC patients. KEGG analysis revealed that GABRP may play an important role in starch and sucrose metabolism and nicotine addiction. Specifically, GABRP expression showed significant positive correlations with the infiltration levels of most types of immune cells, as well as immune checkpoint molecules expression.

Conclusion: Up-regulation of GABRP in LUSC could be severed as a prognostic marker and a potential target for immunotherapy in LUSC.

[This corrects the article DOI: 10.2147/PGPM.S346187.].

Background: The apolipoprotein E (ApoE) genetic variation may contribute to the development of Cerebral Infarction (CI). Serum lipid levels are known risk factors for CI, but the effect of the ApoE gene polymorphism on lipid metabolism remains unclear. This retrospective cohort study was designed to determine the role of ApoE genotypes in CI risk and the relationships between ApoE gene polymorphism and serum lipid levels among the population of northwest China.

Patients and methods: 517 CI patients and 517 non-CI controls were enrolled in the study. Polymerase chain reaction and hybridization were utilized to determine the ApoE gene polymorphisms.

Results: The ε3/ε4 genotype and ε4 allele frequency were significantly higher in CI patients than in controls. When stratified by age and sex, statistically significant differences in the distribution and frequency of the ε3/ε4 genotype and ε4 allele were found between patients and controls. Compared to ε2 carriers, ε4 carriers had significantly lower ApoE levels and higher low-density lipoprotein cholesterol (LDL-C), ApoB and ApoB/ApoA-I levels in both two groups. Additionally, control participants with ε4 carriers had significantly higher levels of lipoprotein and total cholesterol (TC) levels than ε2 carriers, while CI patients with ε4 carriers had a significantly lower level of ApoA-I. After adjusting for other established risk factors, drinking, hypertension, lipoprotein, triglycerides (TG) and ε4 allele were significant independent risk factors for CI, which was shown to be associated with a nearly two-fold CI risk.

Conclusion: This study demonstrated that ε4 allele is independent risk factors for CI among patients in Northwest China. ApoE polymorphism was associated with CI, which was partly mediated through blood lipids and may also be mediated through non-lipid pathways. These data might be of great clinical significance in individualized preventive and therapeutic strategies.

Purpose: Tuberculosis (TB) is known to result from a complex interaction between the host immune response and Mycobacterium infection. The transporter associated with antigen processing (TAP) plays an important role in the processing and presentation pathways for the Mycobacterium tuberculosis (M. tb) antigen. To investigate the possible association of the TAP1 and TAP2 genes with TB.

Patients and methods: A total of 449 TB patients and 435 control subjects were included in this study, and single nucleotide polymorphisms (SNPs) in the TAP gene, as well as TAP1 and TAP2 alleles, were genotyped.

Results: TAP gene association analysis of TB diseases showed that rs41551515-T in the TAP1 gene was significantly associated with susceptibility to TB (P=7.96E-04, OR=4.124, 95% CI: 1.683-10.102), especially pulmonary TB (PTB, P=6.84E-04, OR=4.350, 95% CI: 1.727-10.945), and the combination of rs1057141-T-rs1135216-C in the TAP1 gene significantly increased the risk of TB susceptibility (P=5.51E-05, OR=10.899, 95% CI: 2.555-46.493). Five novel TAP1 alleles were detected in Yunnan Han people, and the allele frequency of TAP1*unknown_3 (rs41555220-rs41549617-rs1057141-rs1135216-rs1057149-rs41551515: C-A-T-C-C-T) was notably increased in all TB patients, including in the PTB and EPTB subgroups, and was significantly associated with the risk of susceptibility to TB. However, no association between the TAP2 gene and TB was found in this study.

Conclusion: Host genetic variants of rs41551515-T and the combination rs1057141-T-rs1135216-C, as well as TAP1*unknown_3 may play a critical role in susceptibility to TB disease.

Purpose: To explore recurrence-risk factors of diffuse large B cell lymphoma (DLBCL) and construct a risk nomogram for predicting recurrence.

Patients and methods: A retrospective analysis was performed on 228 DLBCL patients who achieved complete remission after R-CHOP treatment between January 2015 and December 2019. Univariate and multivariate analyses were applied to identify recurrence-related risk factors from the pretreatment evaluation factors covering patients' demographic characteristics, clinical manifestations, serological indicators, pathological and immunohistochemical results. A nomogram was developed based on the above results and validated by the concordance index (C-index), the receiver operating characteristic (ROC) curve, and the calibration curve.

Results: The training and validation cohorts consisted of 160 and 68 patients (randomized by 7:3). Of the whole cohort, 50 of 228 (21.9%) cases recurred during follow-up. Three recurrence-risk factors including BCL2 expression (P = 0.027), CD10 expression (P = 0.021), LDH level (P = 0.004) were identified from multivariate analysis and entered the final nomogram. The C-index of the nomogram was 0.815 in training cohort and 0.797 in the validation cohort, higher than that of IPI system (0.699) and NCCN-IPI system (0.709). And the 1-year, 2-year, 3-year, and 4-year areas under ROC (AUC) were 0.812, 0.850, 0.837, and 0.801, respectively. The calibration curves also showed a good discrimination capability and accuracy.

Conclusion: The novel nomogram incorporating the three independent risk factors (BCL2 expression, CD10 expression and LDH level) provided a valuable tool for predicting DLBCL recurrence.