Approaches to functionally validate candidate genetic variants involved in colorectal cancer predisposition
Bonjoch, Laia and Mur, Pilar and Arnau-Collell, Coral and Vargas-Parra, Gardenia and Shamloo, Bahar and Franch-Expósito, Sebastia and Pineda, Marta and Capellà, Gabriel and Erman, Batu and Castellví-Bel, Sergi (2019) Approaches to functionally validate candidate genetic variants involved in colorectal cancer predisposition. Molecular Aspects of Medicine . ISSN 0098-2997 (Print) 1872-9452 (Online) Published Online First http://dx.doi.org/10.1016/j.mam.2019.03.004
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Official URL: http://dx.doi.org/10.1016/j.mam.2019.03.004
Most next generation sequencing (NGS) studies identified candidate genetic variants predisposing to colorectal cancer (CRC) but do not tackle its functional interpretation to unequivocally recognize a new hereditary CRC gene. Besides, germline variants in already established hereditary CRC-predisposing genes or somatic variants share the same need when trying to categorize those with relevant significance. Functional genomics approaches have an important role in identifying the causal links between genetic architecture and phenotypes, in order to decipher cellular function in health and disease. Therefore, functional interpretation of identified genetic variants by NGS platforms is now essential. Available approaches nowadays include bioinformatics, cell and molecular biology and animal models. Recent advances, such as the CRISPR-Cas9, ZFN and TALEN systems, have been already used as a powerful tool with this objective. However, the use of cell lines is of limited value due to the CRC heterogeneity and its close interaction with microenvironment. Access to tridimensional cultures or organoids and xenograft models that mimic the in vivo tissue architecture could revolutionize functional analysis. This review will focus on the application of state-of-the-art functional studies to better tackle new genes involved in germline predisposition to this neoplasm.
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