Organoid-based platform for variant interpretation in colorectal cancer

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy (1.8M cases/year) and second leading cause of cancer deaths (0.9M deaths/year). Hereditary CRC syndromes are frequent (1:300) and explain 3-5% of CRCs and about 10% of CRCs diagnosed before age 50. The increasing application of next generation sequencing to hereditary cancer diagnosis and clinical oncology has caused an exponential increase in the identification of genetic variants of unknown significance. Their interpretation is relevant and urgent since clinical decisions depend on it. However, the clinical relevance of functional studies is low due to their inefficiency, low reliability, and use of inadequate models/assays. Organ-VIP will surpass the barriers found when using and implementing functional assays for variant interpretation in hereditary CRC genes, some of which are prognostic and therapeutic markers.

 

Preliminary and promising results from our laboratory, coupled with state-of-the-art technological and methodological applications, and innovative concepts, supports the development of a high-throughput screening system to solve variant interpretation in hereditary CRC genes.

​

We plan to: i) use models that represent clinical reality (genome-edited human normal cells and colon organoids); ii) optimize end-point assays to maximise performance and agreement with clinical evidence; iii) upgrade the system for high-throughput screenings; iv) functionally assess all coding variants in hereditary CRC genes; and v) develop an informatic tool that implements the obtained results and gene-specific classification guidelines to facilitate clinical translation.

 

Organ-VIP will solve variant interpretation in germline and somatic testing in oncology. It will lead to improved precision medicine, having a clear impact for clinicians, patients and society by reducing CRC incidence, morbidity and mortality. The developed methodologies will open new opportunities to other cancers and genetic diseases.