Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

Tarek M.A. Abdel-Fatah; Roslin Russell; Nada Albarakati; David J. Maloney; Dorjbal Dorjsuren; Oscar M. Rueda; Paul Moseley; Vivek Mohan; Hongmao Sun; Rachel Abbotts; Abhik Mukherjee; Devika Agarwal; Jennifer L. Illuzzi; Ajit Jadhav; Anton Simeonov; Graham Ball; Stephen Chan; Carlos Caldas; Ian O. Ellis; David M. Wilson; Srinivasan Madhusudan

doi:10.1016/j.molonc.2014.04.009

Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

Tarek M.A. Abdel-Fatah
, Roslin Russell
, Nada Albarakati
, David J. Maloney
, Dorjbal Dorjsuren
, Oscar M. Rueda
, Paul Moseley
, Vivek Mohan
, Hongmao Sun
, Rachel Abbotts
, Abhik Mukherjee
, Devika Agarwal
, Jennifer L. Illuzzi
, Ajit Jadhav
, Anton Simeonov
, Graham Ball
, Stephen Chan
, Carlos Caldas
, Ian O. Ellis
, David M. Wilson

Srinivasan Madhusudan^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

135 Scopus citations

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, 894ER 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.

Original language	English
Pages (from-to)	1326-1338
Number of pages	13
Journal	Molecular Oncology
Volume	8
Issue number	7
DOIs	https://doi.org/10.1016/j.molonc.2014.04.009
State	Published - 1 Oct 2014
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2014 Federation of European Biochemical Societies.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Breast cancer
Drug target
FEN1
Predictive factor
Prognostic factor

Access to Document

10.1016/j.molonc.2014.04.009

Cite this

Abdel-Fatah, T. M. A., Russell, R., Albarakati, N., Maloney, D. J., Dorjsuren, D., Rueda, O. M., Moseley, P., Mohan, V., Sun, H., Abbotts, R., Mukherjee, A., Agarwal, D., Illuzzi, J. L., Jadhav, A., Simeonov, A., Ball, G., Chan, S., Caldas, C., Ellis, I. O., ... Madhusudan, S. (2014). Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer. Molecular Oncology, 8(7), 1326-1338. https://doi.org/10.1016/j.molonc.2014.04.009

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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, 894ER 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.",

keywords = "Breast cancer, Drug target, FEN1, Predictive factor, Prognostic factor",

author = "Abdel-Fatah, \{Tarek M.A.\} and Roslin Russell and Nada Albarakati and Maloney, \{David J.\} and Dorjbal Dorjsuren and Rueda, \{Oscar M.\} and Paul Moseley and Vivek Mohan and Hongmao Sun and Rachel Abbotts and Abhik Mukherjee and Devika Agarwal and Illuzzi, \{Jennifer L.\} and Ajit Jadhav and Anton Simeonov and Graham Ball and Stephen Chan and Carlos Caldas and Ellis, \{Ian O.\} and Wilson, \{David M.\} and Srinivasan Madhusudan",

note = "Publisher Copyright: {\textcopyright} 2014 Federation of European Biochemical Societies.",

year = "2014",

month = oct,

day = "1",

doi = "10.1016/j.molonc.2014.04.009",

language = "אנגלית",

volume = "8",

pages = "1326--1338",

journal = "Molecular Oncology",

issn = "1574-7891",

publisher = "John Wiley and Sons Ltd",

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Abdel-Fatah, TMA, Russell, R, Albarakati, N, Maloney, DJ, Dorjsuren, D, Rueda, OM, Moseley, P, Mohan, V, Sun, H, Abbotts, R, Mukherjee, A, Agarwal, D, Illuzzi, JL, Jadhav, A, Simeonov, A, Ball, G, Chan, S, Caldas, C, Ellis, IO, Wilson, DM & Madhusudan, S 2014, 'Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer', Molecular Oncology, vol. 8, no. 7, pp. 1326-1338. https://doi.org/10.1016/j.molonc.2014.04.009

TY - JOUR

T1 - Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

AU - Abdel-Fatah, Tarek M.A.

AU - Russell, Roslin

AU - Albarakati, Nada

AU - Maloney, David J.

AU - Dorjsuren, Dorjbal

AU - Rueda, Oscar M.

AU - Moseley, Paul

AU - Mohan, Vivek

AU - Sun, Hongmao

AU - Abbotts, Rachel

AU - Mukherjee, Abhik

AU - Agarwal, Devika

AU - Illuzzi, Jennifer L.

AU - Jadhav, Ajit

AU - Simeonov, Anton

AU - Ball, Graham

AU - Chan, Stephen

AU - Caldas, Carlos

AU - Ellis, Ian O.

AU - Wilson, David M.

AU - Madhusudan, Srinivasan

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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, 894ER 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.

AB - 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, 894ER 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.

KW - Breast cancer

KW - Drug target

KW - FEN1

KW - Predictive factor

KW - Prognostic factor

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SN - 1574-7891

VL - 8

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EP - 1338

JO - Molecular Oncology

JF - Molecular Oncology

IS - 7

ER -

Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

Abstract

Bibliographical note

UN SDGs

Keywords

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