Abstract 47: Identifying genetic vulnerabilities of chromosome 4p large copy number variants in triple negative breast cancer
Authors: Schwartz Michael , Dandage Rohan , Karam Lynn , Pacis Alain , Kuasne Hellen , Fortier Anne-Marie , Huang Sidong , Bourque Guillaume , Hart Traver , Kuzmin Elena , Park Morag 
Published: June 2022

Triple Negative Breast Cancer (TNBC) is characterized by the absence of common oncogenic drivers, limiting its treatment options; however, it exhibits recurrent large chromosomal deletions. We previously showed that chromosome 4p (chr4p) loss is a frequently observed large copy number variant in TNBC and is associated with poor prognosis. We also showed that chr4p deletion is an early event in tumor evolution and confers on cells a proliferative advantage. Here, we set out to uncover the genetic vulnerabilities associated with chr4p deletion in TNBC to identify novel therapeutic avenues for TNBC and enhance our understanding of the genetic mechanisms that maintain chr4p deletion in the genome. Whole genome sequence analysis of our TNBC Primary Tumor(PT)/Patient-Derived Xenograft (PDX) panel identified samples with copy neutral and deletion status of chr4p. These deletion regions span a large fraction of the chr4p arm. RNAseq analysis revealed that chr4p deletion is functionally significant since gene expression of ~80% of genes was reduced upon chr4p deletion. Chr4p deletion was associated with global transcriptomic changes and differentially expressed genes were enriched for proliferation, DNA replication, cell migration, activation of the innate immune response and protein translation. PDX-derived cell models from these samples showed lentiviral infectivity based on a control lentivirus expressing GFP. Additionally, these PDX cell models were shown to be editable using CRISPR-Cas9 through the targeting of core essential genes. We will use a pooled CRISPR-Cas9 approach to systematically screen for genetic vulnerabilities in TNBC PDX-derived cell models harbouring chr4p copy neutral or deletion state. To further investigate the genetic mechanisms buffering chr4p loss, we have leveraged publicly-available CRISPR-Cas9 genome-wide genetic screen data from the Cancer DepMap to identify putative synthetic lethal (pSL) partners with chr4p deletion in TNBC. This was accomplished by developing regression models and integrating them with results from established methods such as drugZ and MAGeCK. We identified pSL partners for chr4p at gene, segmental and arm levels. pSLs were enriched for mitochondrial, protein translation and proliferation pathways. We will validate the top candidates from these analyses in our cohort of chr4p deletion and chr4p copy neutral TNBC PDX-derived cell models and integrate them with the pooled CRISPR screens. Together, this work aims to reveal potential TNBC-specific therapeutic avenues for precision oncology.

Citation Format: Michael Schwartz, Rohan Dandage, Lynn Karam, Alain Pacis, Hellen Kuasne, Anne-Marie Fortier, Sidong Huang, Guillaume Bourque, Traver Hart, Elena Kuzmin, Morag Park. Identifying genetic vulnerabilities of chromosome 4p large copy number variants in 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 47.