Journal of Personalized Medicine

Background: Pharmacogenetic markers associated with the need to switch patients from methotrexate (MTX) to biologic agents in moderate-to-severe psoriasis remain insufficiently studied. The pharmacokinetics of MTX depend on the individual characteristics of the patient, as well as on the function of specific transporters and enzymes involved in its absorption, distribution, metabolism, and elimination; therefore, polymorphisms in genes encoding these proteins may be considered pharmacogenetic predictors of MTX intolerance or insufficient efficacy. This study aimed to investigate genetic variants associated with MTX intolerance or insufficient efficacy leading to therapy switch. Methods: A total of 80 patients with moderate-to-severe psoriasis were included: 43 who required switching from MTX to biologics and 37 who continued MTX therapy. Twelve polymorphisms in transporter and metabolism-related genes (ABCB1 (rs1045642), MTHFR (rs1801133), ABCB1 (rs1128503), ABCC2 (rs3740066), ABCC2 (rs717620), ABCG2 (rs2231137), GSTP1 (rs1695), SLC19A1 (rs1051266), COL18A1 (rs9977268), SLCO1B1 (rs2306283), SLCO1B1 (rs4149056), and ABCB1 (rs2229109)) were analyzed using next-generation sequencing. Results: Significant differences in genotype frequencies were observed for SLC19A1 rs1051266 (p = 0.03) and COL18A1 rs9977268 (p = 0.02). Carriers of the T allele in both genes were more frequent among patients requiring biologic therapy, suggesting a possible association with MTX intolerance or reduced efficacy. Conclusions: The study revealed an association between polymorphisms in the SLC19A1 rs1051266 and COL18A1 rs9977268 genes and the need to switch from MTX to biologic therapy in patients with moderate-to-severe psoriasis. These findings suggest that carriers of the C allele in these genes may have an increased risk of methotrexate intolerance.

Objective(s): To delineate the somatic mutational landscape of follicular thyroid carcinoma (FTC) from a large, real-world cohort to identify molecular subtypes and actionable targets for personalized therapeutic interventions. Methods: Genomic and clinical data for 168 FTC samples were retrieved from the AACR Project GENIE^® registry via cBioPortal. This study assessed mutation frequencies, copy number alterations, and subgroup differences (primary vs. metastatic; adult vs. pediatric) using statistical tests. Results: NRAS was the most common mutation (33.9%), followed by TERT (22.6%), DICER1 (15.5%), HRAS (11.9%), and PTEN (10.7%). DICER1 mutations were significantly enriched in pediatric cases (44.4% vs. 4.6% in adults, p < 0.001), while TERT mutations were exclusive to adults (42%). NRAS mutations were more frequent in metastatic tumors (42.4%) than primary tumors (29.2%). Conclusions: FTC tumorigenesis is driven by distinct molecular pathways, with significant heterogeneity between pediatric and adult patients as well as primary and metastatic disease. These findings underscore the necessity of molecular profiling for patient stratification and provide a strong rationale for developing personalized treatment strategies to improve clinical outcomes.

Objective(s): To characterize the somatic mutational landscape of laryngeal squamous cell carcinoma (LSCC) using AACR Project GENIE data to identify potential biomarkers for tumor progression and guide precision therapy. Methods: Clinical and genomic data from 135 LSCC samples (primary and metastatic) were analyzed from the AACR Project GENIE database. Mutations were compared by tumor site and gender using chi-squared and Mann–Whitney U tests; co-occurrence and mutual-exclusivity analyses were performed. Results: TP53 mutations were most common (89.6%), followed by KMT2D (27.4%), FAT1 (20.7%), and NOTCH1 (20.7%). CDK8 mutations were enriched in females (p = 0.011) and ATP8B1 in males (p = 0.013). DMD mutations characterized primary tumors (p = 0.049), whereas ATP8B1 and SAMD9L were linked to metastases (p < 0.001). The cohort was 85.9% male and 71.5% White; 59.2% of samples were primary and 39.2% recurrent/metastatic. Co-occurrence analysis identified distinct molecular subtypes. The identification of distinct molecular subtypes and gender-specific mutations, such as CDK8 in females and ATP8B1 in males, suggests potential avenues for tailored therapeutic interventions. Conclusions: LSCC exhibits marked genetic heterogeneity dominated by TP53 alterations. ATP8B1 and SAMD9L mutations may mark metastatic disease, and gender-specific mutations suggest avenues for personalized therapy. These insights support development of targeted strategies, including immunotherapies such as pembrolizumab in TP53-altered tumors. These insights into the genomic heterogeneity of LSCC lay the groundwork for developing targeted therapeutic strategies and patient stratification, ultimately advancing a personalized medicine approach to this disease.