Descrizione del progetto
Organoidi per l’interpretazione della patogenicità dei geni tumorali
Il sequenziamento di nuova generazione (next generation sequencing, NGS) è una tecnologia ad alte prestazioni che ha rivoluzionato le scienze biologiche, fornendo informazioni senza precedenti sulle variazioni genetiche in oncologia. Al tempo stesso, la classificazione di queste informazioni, spesso dalla rilevanza incerta, rappresenta una notevole sfida medica. Il progetto Organ-VIP, finanziato dall’UE, mira a superare i limiti associati agli attuali campioni funzionali utilizzati per interpretare le variazioni genetiche nel cancro. Concentrando l’attenzione sui geni del tumore del colon-retto (colorectal cancer, CRC), i ricercatori svilupperanno una piattaforma di screening basata su organoidi per analizzare la patogenicità funzionale delle variazioni genetiche. Le prospettive ad alte prestazioni della tecnologia aprono nuove opportunità per la sua implementazione regolare nella valutazione di geni CRC nuovi e noti.
Obiettivo
Implementation of next generation sequencing to genetic diagnosis and precision medicine has revolutionized the fields of hereditary cancer and oncology, increasing exponencially the identification of genetic variants of uncertain significance. Their classification is one of the most relevant and urgent challenges we face, since decision-making in the clinics depends on it. Evidence obtained from empirical functional studies is essential to reach a definitive classification; however, clinical relevance of such studies is currently low due to lack of standardized tests, use of inadequate models, and tediousness and cost- and time-inefficiency of available assays.
Organ-VIP aims at surpassing the barriers we face when using and implementing functional assays for the interpretation of genetic variants in colorectal cancer (CRC) genes. State-of-the-art methodological and conceptual developments will facilitate the development of a screening platform to interpret the pathogenicity of variants in any CRC gene. To do so, we aim to: i) Use a model that faithfully represents the target tissue and genetic context (CRISPR/Cas9-edited human normal colon organoids); ii) Optimize end-point assay(s) to maximize performance, implementation, robustness and agreement with clinical evidence; iii) Assess genetic variants in hereditary CRC and polyposis genes; and iv) Calibrate the results for implementation in variant classifiers.
Organ-VIP integrates clinical aspects, molecular and cell biology, next generation sequencing, and advanced bioinformatics analysis. The platform will not only be useful for variant interpretation in germline and somatic testing, but also for functional evaluation of new candidate CRC genes. In the longer term, Organ-VIP will become high-throughput by the implementation of saturation genome editing, high-throughput organoid culture, automation of sampling, and implementation of artificial intelligence.
Campo scientifico
Not validated
Not validated
- natural sciencescomputer and information sciencesartificial intelligence
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesbiological sciencescell biology
- medical and health sciencesclinical medicineoncologycolorectal cancer
- medical and health scienceshealth sciencespersonalized medicine
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
08908 L'Hospitalet De Llobregat
Spagna