DNA polymerase B deficiency is linked to aggressive breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression in multiple cohorts

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Abdel-Fatah, TMA, Russell, R, Agarwal, D, Moseley, P, Abayomi, M, Perry, C, Albarakati, N, Ball, G ORCID: https://orcid.org/0000-0001-5828-7129, Chan, S, Caldas, C, Ellis, IO and Madhusudan, S, 2014. DNA polymerase B deficiency is linked to aggressive breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression in multiple cohorts. Molecular Oncology, 8 (3), pp. 520-532. ISSN 1574-7891

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Official URL: http://dx.doi.org/10.1016/j.molonc.2014.01.001

Abstract

Short arm of chromosome 8 is a hot spot for chromosomal breaks, losses and amplifications in breast cancer. Although such genetic changes may have phenotypic consequences, the identity of candidate gene(s) remains to be clearly defined. Pol β gene is localized to chromosome 8p12 - p11 and encodes a key DNA base excision repair protein. Pol β may be a tumour suppressor and involved in breast cancer pathogenesis. We conducted the first and the largest study to comprehensively evaluate pol β in breast cancer. We investigated pol β gene copy number changes in two cohorts (n=128 & n=1952), pol β mRNA expression in two cohorts (n=249 & n=1952) and pol β protein expression in two cohorts (n=1406 & n=252). Artificial neural network analysis for pol β interacting genes was performed in 249 tumours. For mechanistic insights, pol β gene copy number changes, mRNA and protein levels were investigated together in 1 28 tumours and validated in 1952 tumours. Low pol β mRNA expression as well as low pol β protein expression was associated high grade, lymph node positivity, pleomorphism, triple negative, basal - like phenotypes and poor survival (ps<0.001). In oestrogen receptor (ER) positive sub - group that received tamoxifen, low pol β protein remains associated with aggressive phenotype and poor survival (ps<0.001). Artificial neural network analysis revealed ER as a top pol β interacting gene. Mechanistically, there was strong positive correlation between pol β gene copy number changes and pol β mRNA expression (p<0.0000001) and between pol β mRNA and pol β protein expression (p<0.0000001). This is the first study to provide evidence that pol β deficiency is linked to aggressive breast cancer and may have prognostic and predictive significance in patients.

Item Type:	Journal article
Publication Title:	Molecular Oncology
Creators:	Abdel-Fatah, T.M.A., Russell, R., Agarwal, D., Moseley, P., Abayomi, M., Perry, C., Albarakati, N., Ball, G., Chan, S., Caldas, C., Ellis, I.O. and Madhusudan, S.
Publisher:	Elsevier
Date:	2014
Volume:	8
Number:	3
ISSN:	1574-7891
Identifiers:	Number Type 10.1016/j.molonc.2014.01.001 DOI
Divisions:	Schools > School of Science and Technology
Record created by:	EPrints Services
Date Added:	09 Oct 2015 09:44
Last Modified:	09 Jun 2017 13:09
URI:	https://irep.ntu.ac.uk/id/eprint/1849