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

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posted on 2022-06-24, 15:12 authored by Nicola CosgroveNicola Cosgrove, Damir VareslijaDamir Vareslija, Stephen KeelanStephen Keelan, Ashuvinee Elangovan, Jennifer M Atkinson, Sinead CocchigliaSinead Cocchiglia, Fiona T Bane, Vikrant Singh, Simon FurneySimon Furney, Chunling Hu, Jodi M Carter, Steven N Hart, Siddhartha Yadav, Matten P Goetz, Arnold HillArnold Hill, Steffi Oesterreich, Adrian V Lee, Fergus J Couch, Leonie YoungLeonie Young
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.

Funding

Breast Cancer Ireland Programme Grant, 18239A01

Science Foundation Ireland Frontiers Award, 19/FFP/6443

Breast Cancer NOW grant, 2018JulPR1094

SFI Strategic Partnership Programme POI, 18/SPP/5322

Breast Cancer NOW Fellowship 2019AugSF1310

National Cancer Institute grant R01 CA225662

National Cancer Institute Outstanding Investigator Award, R35 CA253187

Breast Cancer Research Foundation

Specialized Program of Research Excellence (SPORE) in breast cancer award to the Mayo Clinic (P50 CA116201)

History

Comments

The original article is available at https://www.nature.com/

Published Citation

Cosgrove N, et al. Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities. Nat Commun. 2022;13(1):514.

Publication Date

26 January 2022

PubMed ID

35082299

Department/Unit

  • Surgery
  • Beaumont Hospital

Research Area

  • Cancer
  • Surgical Science and Practice

Publisher

Springer Science and Business Media LLC

Version

  • Published Version (Version of Record)