RESUMEN
BACKGROUND: TMPRSS2-ERG (T2E) fusion is highly related to aggressive clinical features in prostate cancer (PC), which guides individual therapy. However, current fusion prediction tools lacked enough accuracy and biomarkers were unable to be applied to individuals across different platforms due to their quantitative nature. This study aims to identify a transcriptome signature to detect the T2E fusion status of PC at the individual level. METHODS: Based on 272 high-throughput mRNA expression profiles from the Sboner dataset, we developed a rank-based algorithm to identify a qualitative signature to detect T2E fusion in PC. The signature was validated in 1223 samples from three external datasets (Setlur, Clarissa, and TCGA). RESULTS: A signature, composed of five mRNAs coupled to ERG (five ERG-mRNA pairs, 5-ERG-mRPs), was developed to distinguish T2E fusion status in PC. 5-ERG-mRPs reached 84.56% accuracy in Sboner dataset, which was verified in Setlur dataset (n = 455, accuracy = 82.20%) and Clarissa dataset (n = 118, accuracy = 81.36%). Besides, for 495 samples from TCGA, two subtypes classified by 5-ERG-mRPs showed a higher level of significance in various T2E fusion features than subtypes obtained through current fusion prediction tools, such as STAR-Fusion. CONCLUSIONS: Overall, 5-ERG-mRPs can robustly detect T2E fusion in PC at the individual level, which can be used on any gene measurement platform without specific normalization procedures. Hence, 5-ERG-mRPs may serve as an auxiliary tool for PC patient management.
Asunto(s)
Neoplasias de la Próstata , Transcriptoma , Masculino , Humanos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Fusión Oncogénica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , ARN Mensajero/genética , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/uso terapéuticoRESUMEN
INTRODUCTION: Targeted therapy is used to treat lung adenocarcinoma caused by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain and rare subtypes (<5%) of non-small cell lung cancer. These subtypes include fusion oncoproteins like anaplastic lymphoma kinase (ALK), ROS1, rearranged during transfection (RET), and other receptor tyrosine kinases (RTKs). The use of diverse selective oral inhibitors, including those targeting rat sarcoma viral oncogene homolog (KRAS) mutations, has significantly improved clinical responses, extending progression-free and overall survival. AREAS COVERED: Resistance remains a critical issue in lung adenocarcinoma, notably in EGFR mutant, echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion, and KRAS mutant tumors, often associated with epithelial-to-mesenchymal transition (EMT). EXPERT OPINION: Despite advancements in next generation EGFR inhibitors and EML4-ALK therapies with enhanced brain penetrance and identifying resistance mutations, overcoming resistance has not been abated. Various strategies are being explored to overcome this issue to achieve prolonged cancer remission and delay resistance. Targeting yes-associated protein (YAP) and the mechanisms associated with YAP activation through Hippo-dependent or independent pathways, is desirable. Additionally, the exploration of liquid-liquid phase separation in fusion oncoproteins forming condensates in the cytoplasm for oncogenic signaling is a promising field for the development of new treatments.
Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/uso terapéutico , Adenocarcinoma del Pulmón/tratamiento farmacológico , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/uso terapéutico , Mutación , Receptores ErbB/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Caso clínico: Varón de 14 años con enfermedad de Coats en su ojo derecho. Agudeza visual (AV) 0,1. Microaneurismas, exudados, edema macular de 959μm y telangiectasias periféricas. Tras 12 meses iniciales con 6 inyecciones de ranibizumab y 3 sesiones de láser argón, persistía edema macular de 553μm y AV 0,2. Después de 4 dosis de aflibercept y otras 2 sesiones de láser, presenta buen perfil foveal y AV 0,5, sin recurrencias desde hace 12 meses. Discusión: El tratamiento con aflibercept combinado con láser argón, resultó efectivo en nuestro paciente con enfermedad de Coats en estadio 2B y edema macular, con respuesta incompleta al ranibizumab (AU)
Clinical case: A 14 year-old boy with Coats disease in his right eye, presented with a visual acuity (VA) of 0.1, micro-aneurysms, exudates, a macular oedema of 959 microns, and peripheral telangiectasias. After 12 months follow-up with 6 ranibizumab injections and 3 sessions of argon laser photocoagulation, the macular oedema remained and VA was 0.2. Following 4 aflibercept injections and another 2 laser sessions, he had a good foveal slope and a VA of 0.5, with no recurrences in the last 12 months. Discussion: Treatment with aflibercept and argon laser was effective in our patient with stage 2B Coats disease and macular oedema unresponsive to ranibizumab (AU)