Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer.
Nirmesh PatelDaniel WeekesKonstantinos DrosopoulosPatrycja GazinskaElodie NoelMamun RashidHasan MirzaJelmar QuistFara Brasó-MaristanySumi MathewRiccardo FerroAna Mendes PereiraCynthia PrinceFarzana NoorErika Francesch-DomenechRebecca MarlowEmanuele de RinaldisAnita GrigoriadisSpiros LinardopoulosPierfrancesco MarraAndrew N J TuttPublished in: Nature communications (2018)
Triple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs). Here, we describe an integrative genomic and RNAi-based approach that identifies and validates gene addictions in TNBCs. CNAs and gene expression alterations are integrated and genes scored for pre-specified target features revealing 130 candidate genes. We test functional dependence on each of these genes using RNAi in breast cancer and non-malignant cells, validating malignant cell selective dependence upon 37 of 130 genes. Further analysis reveals a cluster of 13 TNBC addiction genes frequently co-upregulated that includes genes regulating cell cycle checkpoints, DNA damage response, and malignant cell selective mitotic genes. We validate the mechanism of addiction to a potential drug target: the mitotic kinesin family member C1 (KIFC1/HSET), essential for successful bipolar division of centrosome-amplified malignant cells and develop a potential selection biomarker to identify patients with tumors exhibiting centrosome amplification.
Keyphrases
- genome wide
- copy number
- cell cycle
- dna methylation
- genome wide identification
- mitochondrial dna
- gene expression
- single cell
- bioinformatics analysis
- induced apoptosis
- dna damage response
- cell therapy
- genome wide analysis
- cell proliferation
- mesenchymal stem cells
- emergency department
- climate change
- bone marrow
- endoplasmic reticulum stress
- signaling pathway
- bipolar disorder
- pi k akt