Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer

Nirmesh Patel, Daniel Weekes, Konstantinos Drosopoulos, Patrycja Gazinska, Elodie Noel, Mamun Rashid, Hasan Mirza, Jelmar Quist, Fara Brasó-Maristany, Sumi Mathew, Riccardo Ferro, Ana Mendes Pereira, Cynthia Prince, Farzana Noor, Erika Francesch-Domenech, Rebecca Marlow, Emanuele de Rinaldis, Anita Grigoriadis, Spiros Linardopoulos, Pierfrancesco Marra and Andrew N. J. Tutt ()
Additional contact information
Nirmesh Patel: King’s College London
Daniel Weekes: King’s College London
Konstantinos Drosopoulos: The Institute of Cancer Research
Patrycja Gazinska: King’s College London
Elodie Noel: King’s College London
Mamun Rashid: King’s College London
Hasan Mirza: King’s College London
Jelmar Quist: King’s College London
Fara Brasó-Maristany: King’s College London
Sumi Mathew: King’s College London
Riccardo Ferro: King’s College London
Ana Mendes Pereira: King’s College London
Cynthia Prince: King’s College London
Farzana Noor: King’s College London
Erika Francesch-Domenech: King’s College London
Rebecca Marlow: King’s College London
Emanuele de Rinaldis: King’s College London
Anita Grigoriadis: King’s College London
Spiros Linardopoulos: The Institute of Cancer Research
Pierfrancesco Marra: King’s College London
Andrew N. J. Tutt: King’s College London

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-03283-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03283-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-03283-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().