Pharmacogenomics & Personalized Medicine最新文献

Background: KRAS mutations are typically mutually exclusive in non-small cell lung cancer (NSCLC), with the G12C mutation being the most common subtype. The coexistence of KRAS and EGFR mutations is exceedingly rare and is typically emerges as a secondary event following acquired resistance to EGFR-targeted therapies. We presented a case of a newly diagnosed NSCLC patient harboring concurrent EGFR L858R and KRAS G12A mutations.

Case presentation: A 64-year-old male with a 30-pack-year smoking history presented with a 3-month history of progressive shortness of breath and chest tightness. Contrast-enhanced chest CT revealed a 5 cm spiculated mass in the right upper lobe, abutting the mediastinum, along with bronchial obstruction, right middle lobe atelectasis, and pleural effusion. A CT-guided transthoracic needle biopsy confirmed lung adenocarcinoma. Next-generation sequencing (NGS) identified a c.2573T>G (p.L858R) mutation in exon 21 of the EGFR gene and a c.35G>C (p.G12A) mutation in exon 2 of the KRAS gene. The patient started first-line therapy with osimertinib combined with pemetrexed/nedaplatin, resulting in a transient partial response, significant resolution of pleural effusion, and partial regression of the primary tumor. However, disease progression occurred within 6 months, marked by the appearance of a new cerebellar metastasis, confirmed by MRI. The patient continued osimertinib maintenance therapy and underwent stereotactic radiotherapy for the brain lesion. Despite initial stabilization, pulmonary progression was observed 11 months after the start of treatment. Due to declining performance status and personal preferences, the patient declined further treatment and was lost to follow-up.

Conclusion: We report a rare case of treatment-naïve lung adenocarcinoma harboring concurrent KRAS G12A and EGFR L858R mutations. The patient achieved only transient disease control following treatment with a third-generation EGFR TKI combined with chemoradiotherapy. Further research to explore optimal therapeutic strategies for such complex molecular profiles is needed.

Background: This study aimed to analyze the expression of thyroid hormone-responsive spot 14 (THRSP) and acetyl-CoA carboxylase alpha (ACACA) proteins in breast cancer tumor tissues and their relationship with clinicopathology and prognosis of breast cancer patients. In addition, a nomogram model to predict the prognosis of breast cancer patients was constructed in this study.

Methods: Retrospective analysis of 202 cases of breast cancer patients who underwent surgical treatment in our hospital from October 2019 to March 2021, and collection of patients' cancer tissues and non-Tumor tissue specimens. Immunohistochemistry was used to detect THRSP and ACACA protein expression. Multivariate COX regression was used to analyze the risk factors affecting the prognosis of breast cancer patients. The "rms" package in R software was used to build a survival nomogram model and evaluate the effectiveness of the model.

Results: The expression of THRSP and ACACA proteins in tumor tissues of breast cancer patients was higher than that in non-tumor tissues (p < 0.05). The expression of THRSP and ACACA proteins in breast cancer patients with lymph node metastasis was higher than that in patients without lymph node metastasis (p < 0.05). Cox regression analysis showed that TNM stage III, lymph node metastasis, high expression of Ki-67, high expression of THRSP, and high expression of ACACA were all risk factors for the prognosis of breast cancer patients (p < 0.05). The C-index of the nomogram model was 0.704 (95% CI: 0.596~0.892). The predicted 1-, 2- and 3-year survival AUCs of this nomogram model were 0.802, 0.769 and 0.770, respectively. The calibration curve showed that the model fit the ideal curve well. Decision curve analysis showed the high clinical utility of the model.

Conclusion: The nomogram model constructed based on THRSP and ACACA proteins may provide a reference value for the prognostic evaluation of breast cancer patients.

This paper systematically reviews recent advances in clopidogrel clinical applications to optimize therapeutic precision and medication safety. Using a literature review methodology, we elucidate clopidogrel's pharmacokinetic properties and pharmacodynamic mechanisms, while evaluating its clinical efficacy and adverse reactions in disease management. Recent studies have emphasized the key role of genetic polymorphisms in regulating the efficacy and safety of clopidogrel. Polymorphisms in the CYP2C19 gene have a significant effect on the metabolism of clopidogrel, with loss-of-function (LOF) alleles (*2, *3) reducing the production of active metabolites, leading to elevated platelet reactivity and increasing the risk of major adverse cardiovascular events (MACE), particularly in the Asian populations, where the prevalence of LoF alleles is as high as 29-35%. In contrast, the gain-of-function allele CYP2C19*17 results in a reduced risk of cardiovascular events but increases the risk of bleeding. This article summarizes the latest research progress and monitoring methods of clopidogrel, and suggests that clinics should combine genotyping and platelet function testing with monitoring of blood levels to optimize treatment and provide data reference for clinical administration of clopidogrel.

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disease that is characterized by progressive proximal muscle weakness and pseudohypertrophy. Currently, genetic diagnosis of DMD relies largely on multiplex ligation-dependent probe analysis (MLPA) and Sanger sequencing to identify pathogenic mutations. This study aimed to confirm the genetic etiology of a boy presenting with clinical manifestations that are highly indicative of DMD. A 14-year-old boy with heart failure and extreme muscle weakness along with his family members was recruited for this study. DNA from each participant was isolated from peripheral blood samples. We used MLPA to detect the deletion or duplication mutations of the DMD gene and Sanger sequencing to verify the missing region of the exon in the proband. Furthermore, the functional role of the mutation was assessed using bioinformatics. We found that the proband carried a small deletion in the DMD gene (c.6808_6811delTTAA). The deletion of those four nucleotides resulted in a frameshift mutation and a premature nonsense codon, which resulted in a truncated dystrophin that lost its most critical function and underwent post-transcriptional degradation. Our study demonstrated that MLPA, in combination with Sanger sequencing, is a reliable and practical approach for the genetic diagnosis of DMD, which is a significant step towards developing personalized therapy.

Background: Neuroblastoma (NB) is a malignancy of neural crest cells that primarily affects children. Single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) gene, a well-conserved gene, have been implicated in tumorigenesis. However, there is currently insufficient evidence to establish the relationship between FTO gene SNPs and susceptibility to NB.

Methods: A TaqMan assay was conducted to examine the potential associations between FTO gene SNPs and the risk of NB in a cohort of 898 patients and 1734 controls from eight medical centers in China. Additionally, stratification analysis was performed to evaluate the relationship between the selected FTO SNPs and the susceptibility to NB among various subgroups.

Results: No significant association was found between the selected FTO polymorphisms and the risk of NB in either the single locus analysis or the combined analysis.

Conclusion: However, our study reveals that individuals with retroperitoneal NB and those with stage III+IV NB are more prone to exhibit FTO SNPs compared to other patients. Moreover, participants with the FTO rs8047395 GG genotype displayed a higher likelihood of developing stage III+IV NB in comparison to other participants.

Background: The family with the sequence similarity 198 member B (FAM198B) has been found to contribute to the progression of gastric cancer (GC). However, the role and molecular mechanism of FAM198B in GC remains poorly understood. This work found a link between FAM198B and quercetin, and the regulatory effect of FAM198B on the MAPK pathway of GC.

Methods: FAM198B expression was identified through multiple public data sets and verified in clinical tissue samples. The associations between FAM198B and the prognosis of patients with GC were analyzed via the Kaplan‒Meier plotter and Cox regression analysis. Gene set enrichment analysis, coexpressed genes, and RNA sequencing were used to explore the related functions and signaling pathways of FAM198B in GC. In vitro assays assessed the effects of FAM198B knockdown on GC cells. FAM198B was found as a quercetin target by the HERB database and in vitro assays.

Results: FAM198B was highly expressed in tissues from GC patients (p<0.001) and was positively associated with poor prognosis (p<0.001) and immune cell infiltration in GC patients. FAM198B knockdown inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells (all p<0.05). In addition, FAM198B knockdown decreased the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.01). Quercetin inhibited FAM198B expression and the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.05).

Conclusion: Quercetin inhibits the proliferation, migration, invasion, and EMT of GC cells by inhibiting the FAM198B/MAPK signaling pathway. These discoveries lay the groundwork for developing the treatment of GC by quercetin and targeting FAM198B. In the future, more preclinical and clinical studies are needed to confirm the efficacy and safety of quercetin and target FAM198B in GC.

Background and purpose: The CYP2C19 enzyme is essential for activation of the antiplatelet drug clopidogrel. Genetic variations in CYP2C19 are known to influence individual drug responses. Here, differences in CYP2C19 alleles, genotypes, and phenotypes in patients with cardiovascular disease from the Yunnan-Guizhou Plateau were systematically surveyed to provide a reference for appropriate treatment approaches.

Methods: The CYP2C19*2, *3, and *17 variants were determined by RT-qPCR in 1934 patients with cardiovascular disease from 10 different areas of the Yunnan-Guizhou Plateau. Clinical data were analyzed using χ² tests.

Results: The proportions of the CYP2C19*1, *2, *3, and *17 alleles in the study cohort were 64.94, 29.81, 4.42, and 0.83%, respectively, while the frequencies of nine observed genotypes (*1/*17, *1/*1, *2/*17, *3/*17, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3) were 1.03, 42.09, 0.57, 0.05, 38.73, 5.95, 8.89, 2.53, and 0.16%, respectively. Four metabolic phenotypes were found in the population, namely, rapid (1.03%), normal (42.09%), intermediate (45.29%), and poor (11.58%) metabolizers. Regional differences in allele and phenotype distribution were observed.

Conclusion: These results represent the first comprehensive profile of CYP2C19 variants in patients with cardiovascular disease from the Yunnan-Guizhou Plateau, offering a valuable genetic reference for the selection of optimal treatment strategies.

Background: Inflammatory myofibroblastic tumor (IMT) in the nasal cavity and sinuses is rare and has special clinical and pathological characteristics with poor prognosis. This study aimed to investigate the clinicopathological and molecular features of primary IMT in the nasal cavity and paranasal sinuses.

Methods: The clinical features, histopathological findings, immunohistochemical findings and results of molecular genetic examination were retrospectively analyzed in 25 patients who were diagnosed with IMT in the nasal cavity and paranasal sinuses.

Results: Tumor tissues were mainly composed of obese spindle-shaped myofibroblasts, fibroblasts, and chronic inflammatory cells. The inflammatory cells included plasma cells, lymphocytes, eosinophils, foam histiocytes and multinuclear giant cells. Immunohistochemical staining showed the tumor was positive to anaplastic lymphoma kinase (ALK) in two patients. ALK fusion mutation was detected by PCR in only 1 patient.

Conclusion: Nasal and paranasal sinus IMTs are rare, exhibit histopathological diversity with low specificity, and require careful differentiation from inflammatory and autoimmune disorders. These tumors demonstrate a worse prognosis compared to IMTs in other anatomic locations, along with a significantly lower rate of ALK gene rearrangement. Identifying molecular target alterations can enhance precision diagnosis and targeted therapeutic strategies.

Background: Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked neurodevelopmental disorder caused by mutations in the solute carrier family 16-member 2 (SLC16A2) gene. This syndrome leads to significant psychomotor disabilities, thyroid dysfunction, and abnormal brain development. This case report describes the genetic cause of AHDS in a male proband and to expanding the mutation spectrum of the SLC16A2 gene.

Methods: A blood specimen was collected from a one-year-old child with delayed development and abnormal thyroid function and this was followed by whole-exome sequencing (WES) was performed on the proband to identify potential genetic mutations. Sanger sequencing was subsequently used to confirm the findings and determine the inheritance pattern of the mutation within the family.

Results: The proband, who presented with developmental delay, thyroid dysfunction, and abnormal brain development, was found to have a novel hemizygous frameshift mutation, c.513_538del (p.Ile172Cysfs*60), in the SLC16A2 gene (NM_006517.5). This mutation was inherited from his asymptomatic mother, confirming the X-linked inheritance pattern. The mutation is classified as likely pathogenic, contributing to the clinical presentation observed in the proband.

Conclusion: This study identified a novel frameshift mutation in the SLC16A2 gene associated with AHDS, thereby expanding the known mutation spectrum of this gene. Given the significant impact of AHDS on neural development and hormone secretion, it is recommended that this gene be included in carrier screening panels in China, particularly for families with a history of related neurodevelopmental disorders.

Background: Pharmacogenomics holds significant promise in improving the efficacy and safety of chemotherapy for childhood cancers. However, the field remains underexplored in Africa, where high genetic diversity and substantial disease burdens, including cancers, create unique challenges. This review investigates the current state of pharmacogenomics research in childhood cancer chemotherapies across Africa, focusing on genetic variations influencing chemotherapy efficacy and adverse drug reactions. It also highlights critical gaps, such as limited infrastructure and insufficient healthcare worker knowledge, and emphasizes the importance of capacity-building initiatives in the region.

Methods: A scoping review was conducted encompassing studies published up to September 2024 that examined pharmacogenomic variations associated with chemotherapies in childhood cancer patients across Africa. The review included laboratory genetic analyses and surveys assessing healthcare workers' knowledge, attitudes, and perceptions regarding pharmacogenomics, particularly in the context of pediatric oncology.

Results: A total of 12 genes were identified across eight studies, including TPMT, CYP3A5, MDR1, MAPT, NUDT15, ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3, ABCC4, and MTHFR. The most studied genes were TPMT and CYP3A5, which are involved in the metabolism of 6-mercaptopurine (6-MP) and vincristine, respectively. These studies spanned five African countries, including Kenya, Egypt, Zimbabwe, Nigeria, Tunisia, and Libya, and focused primarily on childhood cancers, particularly acute lymphoblastic leukemia. Chemotherapies frequently studied were 6-MP (reported in five studies), vincristine, cyclophosphamide, and methotrexate. Knowledge of pharmacogenomics among healthcare workers in Africa remains low, though a positive attitude towards its clinical applications was observed.

Conclusion: Pharmacogenomic variants, such as TPMT*3A, 3C, and CYP3A53, *6, significantly impact drug metabolism in African children with cancer. However, research remains regionally limited, and gaps in infrastructure and healthcare worker training persist. Expanding research efforts and improving pharmacogenomics capacity through pharmacist training and capacity-building initiatives are essential to advancing personalized medicine in Africa, ultimately improving treatment outcomes for pediatric cancer patients.