Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer

Stefano Annunziato,Roebi De Bruijn,Bjørn Siteur,Marieke Van De Ven,Jos Jonkers,Ivo J Huijbers,Federica Ferrante,Catrin Lutz,Lodewyk F A Wessels,Martine H Van Miltenburg,Eline Van Der Burg,François Vaillant,Chiara S Brambillasca,Jane E Visvader,Geoffrey J Lindeman,Julian R De Ruiter,Bas Van Gerwen,Anne Paulien Drenth,Linda Henneman

doi:10.1038/s41467-019-08301-2

Abstract

BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. Validation of these candidates requires novel approaches for high-throughput in vivo perturbation of gene function. Here we develop genetically engineered mouse models (GEMMs) of BRCA1-deficient breast cancer that permit rapid introduction of putative drivers by either retargeting of GEMM-derived embryonic stem cells, lentivirus-mediated somatic overexpression or in situ CRISPR/Cas9-mediated gene disruption. We use these approaches to validate Myc, Met, Pten and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis. Iterative mouse modeling and comparative oncogenomics analysis show that MYC-overexpression strongly reshapes the CNA landscape of BRCA1-deficient mammary tumors and identify MCL1 as a collaborating driver in these tumors. Moreover, MCL1 inhibition potentiates the in vivo efficacy of PARP inhibition (PARPi), underscoring the therapeutic potential of this combination for treatment of BRCA1-mutated cancer patients with poor response to PARPi monotherapy.

Highlights

BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes
We developed a novel genetically engineered mouse models (GEMMs) (WapCre;Brca1F/F;Trp53F/F, WB1P) in which mammary-specific expression of Cre is driven by the whey acidic protein (Wap) gene promoter
We validated MYC, MET, PTEN, and RB1 as bona fide drivers of BRCA1-associated tumorigenesis and showed that MYC overexpression dramatically changes the mutational landscape of the resulting tumors

Summary

Introduction

BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. The high degree of genomic instability in BRCAdeficient TNBCs results in large numbers of CNAs harboring tens-to-thousands of genes, which complicates the identification of putative cancer drivers To address this issue, several computational approaches have been developed to identify minimal regions that are recurrently gained or lost across tumors[3,4,5,6]. We have previously used comparative oncogenomics analyses to identify driver genes that were frequently aberrantly amplified or deleted in both mouse and human BRCA1-deficient TNBCs, including the proto-oncogene MYC and the tumor suppressor RB110 It is currently still unclear how exactly these putative drivers of BRCA1-deficient TNBC contribute to tumorigenesis, and how they may influence the mutational landscape of the resulting tumors. By applying comparative oncogenomics to a combined set of germline and somatic BRCA1deficient TNBCs with MYC overexpression, we identify MCL1 as a key driver and a therapeutic target in these tumors

Methods

Results

Conclusion