DNA polymerase β deficiency is linked to aggressive breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression in multiple cohorts.
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 128 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.
Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
Tarek M A
TM
Abdel-Fatah
Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Roslin
R
Russell
School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
Devika
D
Agarwal
Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
Paul
P
Moseley
Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
Michael Ayotunde
MA
Abayomi
Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
Christina
C
Perry
Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
Nada
N
Albarakati
School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
Graham
G
Ball
Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
Stephen
S
Chan
Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Carlos
C
Caldas
Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
Ian O
IO
Ellis
Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK; Division of Oncology, School of Medicine, University of Nottingham, Nottingham NG51PB, UK. Electronic address: srinivasan.madhusudan@nottingham.ac.uk.
Srinivasan
S
Madhusudan
D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D019951:DNA Polymerase beta / Q000032:analysis / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D019951:DNA Polymerase beta
Breast cancer; Pol β; Predictive factor; Prognostic factor