A Key Genomic Subtype Associated with Lymphovascular Invasion in Invasive Breast Cancer

Kurozumi, Sasagu; Joseph, Chitra; Alsaeed, Sami; Kariri, Yousif; Aljohani, Abrar; Raafat, Sara; Alsaleem, Mansour; Ogden, Angela; Johnston, Simon; Aleskandarany, Mohammed A; Fujii, Takaaki; Shirabe, Ken; Caldas, Carlos; Ashankyty, Ibraheem; Dalton, Leslie; Ellis, Ian O; Desmedt, Christine; Green, Andrew R; Mongan, Nigel P; Rakha, Emad A

Abstract

Background: Lymphovascular invasion (LVI) is associated with the development of metastasis in invasive breast cancer (BC). However, the complex molecular mechanisms of LVI, which overlap with other oncogenic pathways, remain unclear. This study, using available large transcriptomic datasets, aims to identify genes associated with LVI in early-stage BC patients.
Methods: Gene expression data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1565) was used as a discovery dataset, and The Cancer Genome Atlas (TCGA; n = 854) cohort was used as a validation dataset. Key genes were identified on the basis of differential mRNA expression with respect to LVI status as characterized by histological review. The relationships among LVI-associated genomic subtype, clinicopathological features and patient outcomes were explored.
Results: A 99-gene set was identified that demonstrated significantly different expression between LVI-positive and LVI-negative cases. Clustering analysis with this gene set further divided cases into two molecular subtypes (subtypes 1 and 2), which were significantly associated with pathology-determined LVI status in both cohorts. The 10-year overall survival of subtype 2 was significantly worse than that of subtype 1.
Conclusion: This study demonstrates that LVI in BC is associated with a specific transcriptomic profile with potential prognostic value.

• Journal Article Type: Article
• Acceptance Date: May 2, 2019
• Online Publication Date: May 22, 2019
• Publication Date: Jun 11, 2019
• Deposit Date: May 3, 2019
• Publicly Available Date: Nov 23, 2019
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Cancer Research UK
• Peer Reviewed: Peer Reviewed
• Volume: 120
• Issue: 12
• Pages: 1129–1136
• DOI: https://doi.org/10.1038/s41416-019-0486-6
• Keywords: invasive breast cancer, lymphovascular invasion, gene signature
• Public URL: https://nottingham-repository.worktribe.com/output/2016864
• Publisher URL: https://www.nature.com/articles/s41416-019-0486-6
• Additional Information: Received: 30 November 2018; Revised: 24 April 2019; Accepted: 2 May 2019; First Online: 22 May 2019; : Ibraheem Alshankyty is a consultant/advisory board in Molecular Diagnostics Lab, College of Applied Med. Sci., KAU. The remaining authors declare no competing interests.; : This study was approved by the Nottingham Research Ethics Committee 2 (Reference title: Development of a molecular genetic classification of breast cancer). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.; : This work was supported by the University of Nottingham (Nottingham Life Cycle 6).; : The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.; : This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).