@article{7221a545b29344bf9ab44eaa23d58842,
title = "Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities",
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.",
author = "Nicola Cosgrove and Damir Vare{\v s}lija and Stephen Keelan and Ashuvinee Elangovan and Atkinson, {Jennifer M.} and Sin{\'e}ad Cocchiglia and Bane, {Fiona T.} and Vikrant Singh and Simon Furney and Chunling Hu and Carter, {Jodi M.} and Hart, {Steven N.} and Siddhartha Yadav and Goetz, {Matthew P.} and Hill, {Arnold D.K.} and Steffi Oesterreich and Lee, {Adrian V.} and Couch, {Fergus J.} and Young, {Leonie S.}",
note = "Funding Information: We are thankful to the patients who generously provided tumor tissue for our studies and to the surgical, pathology, and tissue bank colleagues for their substantial assistance and support. This research was supported in part by the Breast Cancer Ireland Programme Grant, 18239A01 (L.S.Y.), Science Foundation Ireland Frontiers Award, 19/FFP/6443 (L.S.Y., A.D.K.H.) Breast Cancer NOW grant, 2018JulPR1094 (L.S.Y., D.V.), SFI Strategic Partnership Programme POI, 18/SPP/5322 (L.S.Y.), Breast Cancer NOW Fellowship 2019AugSF1310 (D.V.), Breast Cancer Research Foundation; National Cancer Institute Outstanding Investigator Award, R35 CA253187 (F.J.C.); National Cancer Institute grant R01 CA225662 (F.J.C.) and a Specialized Program of Research Excellence (SPORE) in breast cancer award to the Mayo Clinic (P50 CA116201) (F.J.C.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-27987-5",
language = "English (US)",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}