title: Gene-expression signature functional annotation of breast cancer tumours in function of age.
abstract: BACKGROUND
  Breast cancer biological characteristics change as age advances. Today, there is a lack of knowledge regarding age-specific molecular alterations that characterize breast tumours, notably in elderly patients. The vast majority of studies that aimed at exploring breast cancer in function of age are based on clinico-pathological data. Gene-expression signatures (GES), which in some ways capture biological information in a non-reductionist manner, represent powerful tools able to explore tumour heterogeneity.
  
  
  METHODS
  Twenty-five GES were used for functional annotation of breast tumours in function of age: five for molecular subtyping, seven for immune response, three for metabolism, seven for critical pathways in cancer and three for prognosis. Affymetrix® genomics datasets were exclusively used to avoid cross-platform normalization issues. Available corresponding clinico-pathological data were also retrieved and analysed.
  
  
  RESULTS
  Fifteen publicly available datasets were pooled for a total of 2378 breast cancer patients (whole cohort), out of whom 1413 were of Caucasian origin. Three age groups were defined: ≤ 40 years (AG1), > 40 to < 70 years (AG2) and ≥ 70 years (AG3). We confirmed that age influenced the incidence of molecular subtypes. We found a significant growing incidence of luminal B and a decreasing kinetics for basal-like in function of age. We showed that AG3 luminal B tumours were less aggressive than AG1 luminal B tumours based on different GES (iron metabolism, mitochondrial oxidative phosphorylation and reactive stroma), recurrence score prognostic GES and histological grade (SBR). Contrary to tumours of young patients, tumours of elderly patients concentrated favourable GES scores: high oestrogen receptor and mitochondrial oxidative phosphorylation, low proliferation, basal-like, glycolysis, chromosomal instability and iron metabolism, and low GES prognostic scores (van't Veer 70-GES, genomic grade index and recurrence score).
  
  
  CONCLUSIONS
  Functional annotation of breast tumours by means of 25 GES demonstrated a decreasing aggressiveness of breast tumours in function of age. This strategy, which can be strengthened by increasing the number of representative GES to gain more insight into biological systems involved in this disease, provides a framework to develop rational therapeutic strategies in function of age.
authors.affiliation: Bioinfomics unit, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. pascal.jezequel@ico.unicancer.fr.|Cancer Genomic Unit, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. pascal.jezequel@ico.unicancer.fr.|INSERM U892, IRT-UN, 8 quai Moncousu, Nantes Cedex, 44007, France. pascal.jezequel@ico.unicancer.fr.|Biopatholgy department, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. pascal.jezequel@ico.unicancer.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Jézéquel
authors.affiliation: Départemental de Vendée - site de Montaigu, Polyvalent medicine service, Centre Hospitalier, 54, rue Saint Jacques, BP 259, Montaigu, 85602, France. zein.sharif@chd-vendee.fr.
authors.forename: Zein
authors.initials: Z
authors.lastname: Sharif
authors.affiliation: Bioinfomics unit, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. Hamza.lasla@ico.unicancer.fr.
authors.forename: Hamza
authors.initials: H
authors.lastname: Lasla
authors.affiliation: Bioinfomics unit, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. Wilfried.gouraud@ico.unicancer.fr.|Cancer Genomic Unit, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. Wilfried.gouraud@ico.unicancer.fr.|INSERM U892, IRT-UN, 8 quai Moncousu, Nantes Cedex, 44007, France. Wilfried.gouraud@ico.unicancer.fr.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gouraud
authors.affiliation: Bioinfomics unit, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. Catherine.guerin@ico.unicancer.fr.|Cancer Genomic Unit, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. Catherine.guerin@ico.unicancer.fr.|INSERM U892, IRT-UN, 8 quai Moncousu, Nantes Cedex, 44007, France. Catherine.guerin@ico.unicancer.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guérin-Charbonnel
authors.affiliation: INSERM U892, IRT-UN, 8 quai Moncousu, Nantes Cedex, 44007, France. Loic.campion@ico.unicancer.fr.|Biostatistics unit, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. Loic.campion@ico.unicancer.fr.
authors.forename: Loïc
authors.initials: L
authors.lastname: Campion
authors.affiliation: Mathematics laboratory, UMR CNRS 6623 et Université de Franche Comté, 16 route de Gray, Besançon Cedex, 25030, France. Stephane.chretien@univ-fcomte.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chrétien
authors.affiliation: Bioinfomics unit, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. Mario.campone@ico.unicancer.fr.|INSERM U892, IRT-UN, 8 quai Moncousu, Nantes Cedex, 44007, France. Mario.campone@ico.unicancer.fr.|Medical oncology service, Integrated Centre for Oncology - René Gauducheau, Bd J. Monod, Nantes, Saint Herblain Cedex, 44805, France. Mario.campone@ico.unicancer.fr.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D011379:Prognosis