Abstract 2947: Surveying the tumor suppressive genetic network underlying chr4p deletion in TNBC

Abstract

Abstract Triple negative breast cancer (TNBC) is a breast cancer subtype lacking targetable biomarkers, resulting in the worst prognosis compared to other breast cancer subtypes. TNBC is characterized by many large copy number variants that result in the deletion and amplifications of many genes, with TP53 being the only common oncogenic driver. Using TCGA data and in-depth functional genomic analysis of TNBC patient-derived xenografts (PDX), our group showed that chr4p is a recurrently deleted region in basal breast cancer, which TNBC is an enriched subtype. This correlated with poor prognosis and a highly proliferative state. Here, we set out to survey the tumor suppressive genetic network underlying the TNBC-specific chr4pdeletion. Using an arrayed CRISPR-enCas12 screening approach, I will generate a panel of mutant cell lines deleted for all protein-coding genes residing within chr4p. MCF10A series of cell lines will be used for mutant cell line construction, because it is an established normal human breast epithelial model system with a normal karyotype to ensure the diploid state ofchr4p and includes other derivatives (MCF10A(-E7-Bcl2)) that show basal anchorage independent growth in 3D to assess cell transformation. The resulting panel of single gene deletion mutant cell lines will be characterized for their effects on proliferation, apoptosis, cell transformation and senescence. Additionally, the tumor suppressive genetic interaction network of chr4p will be mapped using a multiplexed CRISPR-enCas12 screening methodology. A dual guide-RNA library will be generated for all protein-coding genes to test all pairwise combinations for tumor suppressive genetic interactions. The proliferation due to double gene deletions will be monitored and compared to single gene deletions to identify tumor suppressive interactions. This study will be the first to systematically identify tumor suppressor genetic network underlying chr4p. Ultimately, it will provide an in-depth understanding of the genetic network of large copy number variants in TNBC and insight into new avenues for precision oncology. Citation Format: Joseph Del Corpo, Rohan Dandage, Lea Harrington, Elena Kuzmin. Surveying the tumor suppressive genetic network underlying chr4p deletion in TNBC [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 2947.