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SPAG5 as a prognostic biomarker and chemotherapy sensitivity predictor in breast cancer: a retrospective, integrated genomic, transcriptomic, and protein analysis

Abdel-Fatah, Tarek M.A.; Agarwal, Devika; Liu, Dong-Xu; Russell, Roslin; Rueda, Oscar M.; Liu, Karen; Xu, Bing; Moseley, Paul M.; Green, Andrew R.; Pockley, Alan G.; Rees, Robert C.; Caldas, Carlos; Ellis, Ian O.; Ball, Graham R.; Chan, Stephen Y.T.

Authors

Tarek M.A. Abdel-Fatah

Devika Agarwal

Dong-Xu Liu

Roslin Russell

Oscar M. Rueda

Karen Liu

Bing Xu

Paul M. Moseley

Alan G. Pockley

Robert C. Rees

Carlos Caldas

Graham R. Ball

Stephen Y.T. Chan



Abstract

Background: Proliferation markers and profiles have been recommended for guiding the choice of systemic treatments for breast cancer. However, the best molecular marker or test to use has not yet been identified. We did this study to identify factors that drive proliferation and its associated features in breast cancer and assess their association with clinical outcomes and response to chemotherapy.
Methods: We applied an artificial neural network-based integrative data mining approach to data from three cohorts of patients with breast cancer (the Nottingham discovery cohort (n=171), Uppsala cohort (n=249), and Molecular Taxonomy of Breast Cancer International Consortium [METABRIC] cohort; n=1980). We then identified the genes with the most effect on other genes in the resulting interactome map. Sperm-associated antigen 5 (SPAG5) featured prominently in our interactome map of proliferation and we chose to take it forward in our analysis on the basis of its fundamental role in the function and dynamic regulation of mitotic spindles, mitotic progression, and chromosome segregation fidelity. We investigated the clinicopathological relevance of SPAG5 gene copy number aberrations, mRNA transcript expression, and protein expression and analysed the associations of SPAG5 copy number aberrations, transcript expression, and protein expression with breast cancer-specific survival, disease-free survival, distant relapse-free survival, pathological complete response, and residual cancer burden in the Nottingham discovery cohort, Uppsala cohort, METABRIC cohort, a pooled untreated lymph node-negative cohort (n=684), a multicentre combined cohort (n=5439), the Nottingham historical early stage breast cancer cohort (Nottingham-HES; n=1650), Nottingham early stage oestrogen receptor-negative breast cancer adjuvant chemotherapy cohort (Nottingham-oestrogen receptor-negative-ACT; n=697), the Nottingham anthracycline neoadjuvant chemotherapy cohort (Nottingham-NeoACT; n=200), the MD Anderson taxane plus anthracycline-based neoadjuvant chemotherapy cohort (MD Anderson-NeoACT; n=508), and the multicentre phase 2 neoadjuvant clinical trial cohort (phase 2 NeoACT; NCT00455533; n=253).
Findings: In the METABRIC cohort, we detected SPAG5 gene gain or amplification at the Ch17q11.2 locus in 206 (10%) of 1980 patients overall, 46 (19%) of 237 patients with a PAM50-HER2 phenotype, and 87 (18%) of 488 patients with PAM50-LumB phenotype. Copy number aberration leading to SPAG5 gain or amplification and high SPAG5 transcript and SPAG5 protein concentrations were associated with shorter overall breast cancer-specific survival (METABRIC cohort [copy number aberration]: hazard ratio [HR] 1·50, 95% CI 1·18–1·92, p=0·00010; METABRIC cohort [transcript]: 1·68, 1·40–2·01, p

Citation

Abdel-Fatah, T. M., Agarwal, D., Liu, D., Russell, R., Rueda, O. M., Liu, K., …Chan, S. Y. (2016). SPAG5 as a prognostic biomarker and chemotherapy sensitivity predictor in breast cancer: a retrospective, integrated genomic, transcriptomic, and protein analysis. Lancet Oncology, 17(7), 1004-1018. https://doi.org/10.1016/S1470-2045%2816%2900174-1

Journal Article Type Article
Acceptance Date Jun 14, 2016
Online Publication Date Jun 14, 2016
Publication Date 2016-07
Deposit Date Oct 19, 2016
Publicly Available Date Mar 29, 2024
Journal The Lancet Oncology
Print ISSN 1470-2045
Electronic ISSN 1474-5488
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 17
Issue 7
Pages 1004-1018
DOI https://doi.org/10.1016/S1470-2045%2816%2900174-1
Public URL https://nottingham-repository.worktribe.com/output/975742
Publisher URL http://www.sciencedirect.com/science/article/pii/S1470204516001741