Project description
Organoids for interpreting the pathogenicity of cancer genes
Next generation sequencing (NGS) is a high-throughput technology that has revolutionised biological sciences, providing unparalleled information on genetic variants in oncology. At the same time, classification of this information, often of uncertain significance, presents a significant medical challenge. The EU-funded Organ-VIP project aims to overcome limitations associated with existing functional assays used to interpret genetic variants in cancer. By focussing on colorectal cancer (CRC) genes, researchers will develop an organoid-based screening platform to analyse the functional pathogenicity of genetic variants. The high-throughput prospects of the technology open new opportunities for its routine implementation in the evaluation of emerging and known CRC genes.
Objective
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.
Fields of science
- 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
Keywords
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
08908 L'Hospitalet De Llobregat
Spain