Colorectal cancer (CRC) is the fourth leading cause of cancer death, being the second most common cancer in women and the third in men. Environmental and genetic factors play a key role in the development of this disease, and 10-20% of the cases correspond to familial or hereditary forms. Although several genes have been causally linked to a predisposition to CRC and/or polyposis, there is still a high proportion of patients with familial and/or early-onset CRC that do not carry pathogenic variants in any of the known hereditary cancer genes.
In the last decades, Next Generation Sequencing (NGS) technologies have boosted the discovery of candidate CRC predisposition genes, and the identification of variants of unknown significance (VUS) in known hereditary cancer genes. However, until the causal link of those candidate genes with cancer is confirmed, and the pathogenic or benign nature of the variants is dilucidated, they lack clinical value. The identification of a pathogenic variant in a cancer predisposition gene significantly improves the clinical management of the individual carrier, through the application of individualised surveillance protocols based on the corresponding cancer risks, and in some cases, of personalized oncologic treatments based on targeted therapies. Variant classification largely relies on clinical data (cosegregation data, tumour molecular features); however, these are often unavailable, leaving the functional experimental evidence to be decisive for variant classification.
The project to be developed by the MSCA-IF grantee is aimed to develop a platform based on genetically modified intestinal organoids for the functional characterization of variants and genes affecting Wnt signalling, BMP/TGF-beta pathway, or DNA repair mechanisms. The specific objectives are: (a) to implement and optimize the intestinal organoid culture, gene editing and gene-specific functional tests in the host lab to study VUS potentially involved in the development of hereditary CRC (hCRC); (b) to assess VUSs in hereditary CRC and polyposis genes affecting the different pathways/mechanisms mentioned above; and (c) to calibrate the obtained functional results for implementation of variant classification guidelines. On the other hand, this fellowship is also focused on the training and development of skills for the development of the Fellow’s professional career.
