Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities

Nicola Cosgrove, Damir Varešlija, Stephen Keelan, Ashuvinee Elangovan, Jennifer M. Atkinson, Sinéad Cocchiglia, Fiona T. Bane, Vikrant Singh, Simon Furney, Chunling Hu, Jodi M. Carter, Steven N. Hart, Siddhartha Yadav, Matthew P. Goetz, Arnold D. K. Hill, Steffi Oesterreich, Adrian V. Lee, Fergus J. Couch () and Leonie S. Young ()
Additional contact information
Nicola Cosgrove: RCSI University of Medicine and Health Sciences
Damir Varešlija: RCSI University of Medicine and Health Sciences
Stephen Keelan: RCSI University of Medicine and Health Sciences
Ashuvinee Elangovan: University of Pittsburgh
Jennifer M. Atkinson: University of Pittsburgh
Sinéad Cocchiglia: RCSI University of Medicine and Health Sciences
Fiona T. Bane: RCSI University of Medicine and Health Sciences
Vikrant Singh: RCSI University of Medicine and Health Sciences
Simon Furney: Royal College of Surgeons in Ireland
Chunling Hu: Mayo Clinic
Jodi M. Carter: Mayo Clinic
Steven N. Hart: Mayo Clinic
Siddhartha Yadav: Mayo Clinic
Matthew P. Goetz: Mayo Clinic
Arnold D. K. Hill: RCSI University of Medicine and Health Sciences
Steffi Oesterreich: University of Pittsburgh
Adrian V. Lee: University of Pittsburgh
Fergus J. Couch: Mayo Clinic
Leonie S. Young: RCSI University of Medicine and Health Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Here we comprehensively dissect genomic, transcriptomic and clinical data in patient-matched longitudinal tumor samples, and unravel distinct transcriptional programs enriched in brain metastasis. We report on subtype specific hub genes and functional processes, central to disease-affected networks in brain metastasis. Importantly, in luminal brain metastases we identify homologous recombination deficiency operative in transcriptomic and genomic data with recurrent breast mutational signatures A, F and K, associated with mismatch repair defects, TP53 mutations and homologous recombination deficiency (HRD) respectively. Utilizing PARP inhibition in patient-derived brain metastatic tumor explants we functionally validate HRD as a key vulnerability. Here, we demonstrate a functionally relevant HRD evident at genomic and transcriptomic levels pointing to genomic instability in breast cancer brain metastasis which is of potential translational significance.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-27987-5 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:13:y:2022:i:1:d:10.1038_s41467-022-27987-5

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

DOI: 10.1038/s41467-022-27987-5

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 ().