Dataset Information

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach.

ABSTRACT: The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine.

SUBMITTER: Jorda P

PROVIDER: S-EPMC7918949 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach.

Jordà Paloma P Toro Rocío R Diez Carles C Salazar-Mendiguchía Joel J Fernandez-Falgueras Anna A Perez-Serra Alexandra A Coll Monica M Puigmulé Marta M Arbelo Elena E García-Álvarez Ana A Sarquella-Brugada Georgia G Cesar Sergi S Tiron Coloma C Iglesias Anna A Brugada Josep J Brugada Ramon R Campuzano Oscar O

Journal of personalized medicine 20210215 2

The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episode ...[more]

PMID: 33671899

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Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. We present the generation and characterization of five distinct MPNST orthoxenograft models for preclinical testing and personalized medicine. Four of the models are patient-derived tumor xenografts (PDTX), two independent MPNSTs from the same NF1 patient and two from different sporadic patients. The fifth model is an orthoxenograft derived from an NF1-related MPNST cell line. All MPNST orthoxenografts were generated by tumor implantation, or cell line injection, next to the sciatic nerve of nude mice, and were perpetuated by 7-10 mouse-to-mouse passages. The models reliably recapitulate the histopathological properties of their parental primary tumors. They also mimic distal dissemination properties in mice. Human stroma was rapidly lost after MPNST engraftment and replaced by murine stroma, which facilitated genomic tumor characterization. Compatible with an origin in a catastrophic event and subsequent genome stabilization, MPNST contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Mutational frequency and type of somatic point mutations were highly variable among the different MPNSTs modeled, but very consistent when comparing primary tumors with matched orthoxenografts generated. Unsupervised cluster analysis and principal component analysis (PCA) using an MPNST expression signature of ~1,000 genes grouped together all primary tumor-orthoxenograft pairs. Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines. Following standardization and extensive characterization and validation, the orthoxenograft models were used for initial preclinical drug testing. Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth. The development of genomically well-characterized preclinical models for MPNST allowed the evaluation of novel therapeutic strategies for personalized medicine.

Dataset Information

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach.

Publications

Malignant Arrhythmogenic Role Associated with <i>RBM20</i>: A Comprehensive Interpretation Focused on a Personalized Approach.

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