title: ERCC1 and telomere status in breast tumours treated with neoadjuvant chemotherapy and their association with patient prognosis.
abstract: Dysfunctional telomeres and DNA damage repair (DDR) play important roles in cancer progression. Studies have reported correlations between these factors and tumour aggressiveness and clinical outcome in breast cancer. We studied the characteristics of telomeres and expression of ERCC1, a protein involved in a number of DNA repair pathways and in telomere homeostasis, to assess their prognostic value, alone or in combination, in 90 residual breast tumours after treatment with neoadjuvant chemotherapy (NCT). ERCC1 status was investigated at different molecular levels (protein and gene expression and gene copy-number variations) by immunohistochemistry, qRT-PCR and quantitative multiplex fluorescent-PCR (QMF-PCR). A comprehensive analysis of telomere characteristics was performed using qPCR for telomere length and qRT-PCR for telomerase (hTERT), tankyrase 1 (TNKS) and shelterin complex (TRF1,TRF2,POT1,TPP1,RAP1andTIN2) gene expression. Short telomeres, highhTERTandTNKSexpression and low ERCC1 protein expression were independently associated with worse survival outcome. Interestingly,ERCC1gains and losses correlated with worse disease-free (p= 0.026) and overall (p= 0.043) survival as compared to survival of patients with normal gene copy-numbers. Unsupervised hierarchical clustering of all ERCC1 and telomere parameters identified four subgroups with distinct prognosis. In particular, a cluster combining low ERCC1,ERCC1gene alterations, dysfunctional telomeres and highhTERTand a cluster with highTNKSand shelterin expression correlated with poor disease-free (HR= 5.41,p= 0.0044) and overall survival (HR= 6.01,p= 0.0023) irrespective of tumour stage and grade. This comprehensive study demonstrates that telomere dysfunction and DDR can contribute synergistically to tumour progression and chemoresistance. These parameters are predictors of clinical outcome in breast cancer patients treated with NCT and could be useful clinically as prognostic biomarkers to tailor adjuvant chemotherapy post-NCT.
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of Medical CytogeneticsCHU Estaing1 place Lucie et Raymond AubracF-63003Clermont-FerrandFrance.
authors: Mathilde
authors: M
authors: Gay-Bellile
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of PathologyJean Perrin Comprehensive Cancer Center 58 rue MontalembertF-63011Clermont-FerrandFrance.
authors: Pierre
authors: P
authors: Romero
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of PathologyJean Perrin Comprehensive Cancer Center 58 rue MontalembertF-63011Clermont-FerrandFrance.
authors: Anne
authors: A
authors: Cayre
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of Medical CytogeneticsCHU Estaing1 place Lucie et Raymond AubracF-63003Clermont-FerrandFrance.
authors: Lauren
authors: L
authors: Véronèse
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of OncogeneticsJean Perrin Comprehensive Cancer Center58 rue MontalembertF-63011Clermont-FerrandFrance.
authors: Maud
authors: M
authors: Privat
authors: Medical and Scientific Affairs Office of Pathology, Ventana Medical Systems, Inc, Roche Group 1910 E Innovation Park Drive Tucson AZ 85755 USA.
authors: Shalini
authors: S
authors: Singh
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of Medical CytogeneticsCHU Estaing1 place Lucie et Raymond AubracF-63003Clermont-FerrandFrance.
authors: Patricia
authors: P
authors: Combes
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Clinical and Translational Research DivisionJean Perrin Comprehensive Cancer Center 58 rue MontalembertF-63011Clermont-FerrandFrance.
authors: Fabrice
authors: F
authors: Kwiatkowski
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Clinical and Translational Research DivisionJean Perrin Comprehensive Cancer Center 58 rue MontalembertF-63011Clermont-FerrandFrance.
authors: Catherine
authors: C
authors: Abrial
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of OncogeneticsJean Perrin Comprehensive Cancer Center58 rue MontalembertF-63011Clermont-FerrandFrance; Biological Resource Center BB-0033-00075, Jean Perrin Comprehensive Cancer Center 58 rue MontalembertF-63011Clermont-FerrandFrance.
authors: Yves-Jean
authors: YJ
authors: Bignon
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of Medical CytogeneticsCHU Estaing1 place Lucie et Raymond AubracF-63003Clermont-FerrandFrance.
authors: Philippe
authors: P
authors: Vago
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of PathologyJean Perrin Comprehensive Cancer Center 58 rue MontalembertF-63011Clermont-FerrandFrance.
authors: Frédérique
authors: F
authors: Penault-Llorca
authors: ERTICA EA4677 Research Team, University of Auvergne, Faculty of Medecine28 place Henri DunantF-63001Clermont-FerrandFrance; Department of Medical CytogeneticsCHU Estaing1 place Lucie et Raymond AubracF-63003Clermont-FerrandFrance.
authors: Andreï
authors: A
authors: Tchirkov
keywords: ERCC1; Telomeres; breast cancer; neoadjuvant chemotherapy; prognosis; residual disease; shelterin; tankyrase; telomerase