Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2 : In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants
Özkan, Selen (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Padilla Sirera, Natàlia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
de la Cruz, Xavier (Institució Catalana de Recerca i Estudis Avançats)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	The present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i. e. , computational estimates of the outcomes of functional assays, can be a good option to address this bottleneck. The application of this idea to the BRCA1/2 variants in the CAGI 5-ENIGMA international challenge has shown promising results. Here, we developed this approach, exploring the predictive performances of the regression models applied to the BRCA1/2 variants for which the values of the homology-directed DNA repair and saturation genome editing assays are available. Our results first showed that we can generate endophenotype estimates using a few molecular-level properties. Second, we show that the accuracy of these estimates is enough to obtain pathogenicity predictions comparable to those of many standard tools. Third, endophenotype-based predictions are complementary to, but do not outperform, those of a Random Forest model trained using variant pathogenicity annotations instead of endophenotype values. In summary, our results confirmed the usefulness of the endophenotype approach for the pathogenicity prediction of the BRCA1/2 missense variants, suggesting different options for future improvements.
Ajuts:	Ministerio de Ciencia e Innovación PID2019-111217RB-I0 Ministerio de Economía, Industria y Competitividad SAF2016-80255-R
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	BRCA1 ; BRCA2 ; Endophenotype ; Breast cancer ; Functional assays ; Pathogenicity predictions ; Homology-directed DNA repair (HDR) ; Molecular diagnosis ; Ovarian cancer ; Protein-specific predictor
Publicat a:	International journal of molecular sciences, Vol. 22 (june 2021) , ISSN 1422-0067

DOI: 10.3390/ijms22126226
PMID: 34207612

20 p, 7.5 MB

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