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

Author

Listed:
  • 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
    University of Pittsburgh)

  • Adrian V. Lee

    (University of Pittsburgh
    University of Pittsburgh)

  • Fergus J. Couch

    (Mayo Clinic)

  • Leonie S. Young

    (RCSI University of Medicine and Health Sciences)

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.

Suggested Citation

  • 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 & Stev, 2022. "Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-27987-5
    DOI: 10.1038/s41467-022-27987-5
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    References listed on IDEAS

    as
    1. Paula D. Bos & Xiang H.-F. Zhang & Cristina Nadal & Weiping Shu & Roger R. Gomis & Don X. Nguyen & Andy J. Minn & Marc J. van de Vijver & William L. Gerald & John A. Foekens & Joan Massagué, 2009. "Genes that mediate breast cancer metastasis to the brain," Nature, Nature, vol. 459(7249), pages 1005-1009, June.
    2. Oscar M. Rueda & Stephen-John Sammut & Jose A. Seoane & Suet-Feung Chin & Jennifer L. Caswell-Jin & Maurizio Callari & Rajbir Batra & Bernard Pereira & Alejandra Bruna & H. Raza Ali & Elena Provenzano, 2019. "Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups," Nature, Nature, vol. 567(7748), pages 399-404, March.
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    Cited by:

    1. Zhe Jiang & YoungJun Ju & Amjad Ali & Philip E. D. Chung & Patryk Skowron & Dong-Yu Wang & Mariusz Shrestha & Huiqin Li & Jeff C. Liu & Ioulia Vorobieva & Ronak Ghanbari-Azarnier & Ethel Mwewa & Maria, 2023. "Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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