| Popis: |
Triple-negative breast cancer (TNBC) is a subtype of breast cancer which lacks the expression of key biomarkers, namely Estrogen and Progesterone receptors and HER2. Therefore, it lacks targeted therapies, resulting in the worst prognosis compared to other breast cancer subtypes. Chromosome 4p (chr4p) loss is recurrent in TNBC, correlates with poor prognosis, is an early event in tumor evolution, and confers a proliferative advantage onto cells. Here, we propose that chr4p loss can be leveraged as a genetic vulnerability of TNBC by identifying its specific synthetic lethal (SL) genetic interactions. An SL interaction occurs when the inactivation of individual genes is tolerated, however, the combined inactivation of the corresponding genes leads to a loss of cellular viability. SL interactions offer promising avenues for precision oncology therapeutic strategies of TNBC. We leveraged the publicly available CRISPR-mediated genome-wide gene inactivation screens (DepMap project) dataset to computationally predict pairwise SL interactions that are specific to individual genes within chr4p, as well as complex SL genetic interactions involving multiple genes spanning large segments of chr4p and the entire chromosome arm. We developed regression models to compare the inactivation effect of a given SL partner gene, between cell lines that harbor chr4p loss and those characterized by a copy-neutral status of chr4p, while effectively accounting for potential confounding effects. We integrated the putative SL interactions identified from these regression models with those identified using other methods, drugZ and MAGECK, therefore, resulting in a robust set of putative SL interactions. We have prioritized the SL interactions for their subsequent experimental validation in TNBC PDX-derived 2D and 3D cell models, which we will carry out using CRISPR-based gene editing. The prediction model and collective set of SL candidates identified in this study is a unique resource for the development of SL-based therapeutic strategies for TNBC and other cancers harboring chr4p loss. Citation Format: Rohan Dandage, Michael Schwartz, Lynn Karam, Traver Hart, Elena Kuzmin. Chromosome arm aneuploidies as genetic vulnerabilities of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6390. |
