title: Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer.
abstract: FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p = 4.89 × 10(-57)), high mitotic index (p = 5.25 × 10(-28)), pleomorphism (p = 6.31 × 10(-19)), ER negative (p = 9.02 × 10(-35)), PR negative (p = 9.24 × 10(-24)), triple negative phenotype (p = 6.67 × 10(-21)), PAM50.Her2 (p = 5.19 × 10(-13)), PAM50. Basal (p = 2.7 × 10(-41)), PAM50.LumB (p = 1.56 × 10(-26)), integrative molecular cluster 1 (intClust.1) (p = 7.47 × 10(-12)), intClust.5 (p = 4.05 × 10(-12)) and intClust. 10 (p = 7.59 × 10(-38)) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p = 4.4 × 10(-16)) and multivariate analysis (p = 9.19 × 10(-7)). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps < 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps < 0.05). In ER positive as well as in ER negative tumours, FEN1 protein overexpression is associated with poor survival in univariate and multivariate analysis (ps < 0.01). In ovarian epithelial cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps < 0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer.
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.affiliation: 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.
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK.
authors.forename: Nada
authors.initials: N
authors.lastname: Albarakati
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Dorjbal
authors.initials: D
authors.lastname: Dorjsuren
authors.affiliation: 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.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Moseley
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mohan
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Hongmao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Abbotts
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Abhik
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
authors.forename: Devika
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Illuzzi
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK; Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK. Electronic address: srinivasan.madhusudan@nottingham.ac.uk.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D045585:Flap Endonucleases / Q000032:analysis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D045585:Flap Endonucleases; C468317:FEN1 protein, human
keywords: Breast cancer; Drug target; FEN1; Predictive factor; Prognostic factor