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

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., 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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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:
NumberType
10.1016/j.molonc.2014.01.001DOI
Divisions: Schools > School of Science and Technology
Depositing User: EPrints Services
Date Added: 09 Oct 2015 09:44
Last Modified: 09 Jun 2017 13:09
URI: http://irep.ntu.ac.uk/id/eprint/1849

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