The clinicomolecular landscape of de novo versus relapsed stage IV metastatic breast cancer

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dc.contributor.author Seltzer, Sean
dc.contributor.author Corrigan, Mark
dc.contributor.author O'Reilly, Seamus
dc.date.accessioned 2020-02-25T12:52:48Z
dc.date.available 2020-02-25T12:52:48Z
dc.date.issued 2020-02-14
dc.identifier.citation Seltzer, S., Corrigan, M. and O'Reilly, S. (2020) ‘The clinicomolecular landscape of de novo versus relapsed stage IV metastatic breast cancer’, Experimental and Molecular Pathology, 114. doi: 10.1016/j.yexmp.2020.104404 en
dc.identifier.volume 114 en
dc.identifier.issn 0014-4800
dc.identifier.uri http://hdl.handle.net/10468/9698
dc.identifier.doi 10.1016/j.yexmp.2020.104404 en
dc.description.abstract Background: de novo metastatic breast cancer (dnMBC) is responsible for 6–10% of breast cancer presentations with increasing incidence and has remained resistant to detection by mammography screening. Recent publications hypothesized that in addition to poor screening uptake, the presentation of dnMBC may be due to its unfavourable biology which remains unknown at the molecular level. Here we investigated the tumour biology of dnMBC in the form of clinicopathology, genomic alterations and differential gene expression to create a comparative landscape of de novo versus relapsed metastatic breast cancer (rMBC). Additionally, to address the current screening limitations, we conducted a preliminary biomarker investigation for early dnMBC detection. Methods: In this retrospective case-control study, gene expression and clinical data were accessed from the Cancer Genome Atlas (TCGA) for primary tumours of treatment-naïve patients with dnMBC (n = 17), rMBC (n = 49), and normal tissue (n = 113). The clinical and histological data were assessed categorically using Fisher's Exact-Test for significance (p < .05), or continuously using the Mann-Whitney Test (p < .05) where appropriate. The differential gene expression analysis was performed using EdgeR's negative binomial distribution model with a false discovery rate (FDR) <0.05. The resulting gene list was analysed manually for roles in metastasis as well as ontologically using STRING-DB with FDR <0.05. Results: dnMBCs showed improved median survival vs rMBC (36 vs. 12 months). dnMBCs were more likely to be hormone receptor positive, less likely to be triple negative with lower histological lymphocytic infiltrate. In terms of genome alterations, dnMBCs had 4-fold increased PTEN mutations and poor survival with ABL2 and GATA3 alterations. Expression-wise, dnMBCs down-regulated TNFa, IL-17 signalling, and chemotaxis, while up-regulating steroid biosynthesis, cell migration, and cell adhesion. Biomarker analysis detected pre-existing and novel breast cancer biomarkers. Conclusion: The comparative tumour landscape revealed significant clinical, pathological and molecular differences between dnMBC and rMBC, indicating that dnMBC may be a separate biological entity to rMBC at the primary level with differing paths to metastasis. Additionally, we provided a list of potential serum biomarkers that may be useful in detecting dnMBC in its pre-metastatic window if such a window exists. en
dc.description.sponsorship Health Research Board (Grant ID: SS-2018-129) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Elsevier B.V. en
dc.rights © 2020, Elsevier Inc. All rights reserved. This manuscript version is made available under the CC BY-NC-ND 4.0 license. en
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/ en
dc.subject Breast cancer en
dc.subject Metastasis en
dc.subject Gene expression en
dc.subject de novo en
dc.subject Biomarkers en
dc.title The clinicomolecular landscape of de novo versus relapsed stage IV metastatic breast cancer en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Mark Corrigan, Medicine, University College Cork, Cork, Ireland. T: +353-21-490-3000 E: mark.corrigan@ucc.ie en
dc.internal.availability Full text available en
dc.check.info Access to this article is restricted until 12 months after publication by request of the publisher. en
dc.check.date 2021-02-14
dc.description.version Accepted Version en
dc.contributor.funder Health Research Board en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Experimental and Molecular Pathology en
dc.internal.IRISemailaddress mark.corrigan@ucc.ie en
dc.internal.bibliocheck In press. Check vol / issue / page range. Amend citation as necessary. en
dc.identifier.eissn 1096-0945


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© 2020, Elsevier Inc. All rights reserved. This manuscript version is made available under the CC BY-NC-ND 4.0 license. Except where otherwise noted, this item's license is described as © 2020, Elsevier Inc. All rights reserved. This manuscript version is made available under the CC BY-NC-ND 4.0 license.
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