title: Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy.
abstract: BACKGROUND
  In breast cancer, gene signatures that predict the risk of metastasis after surgical tumor resection are mainly indicative of early events. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery.
  
  
  METHODS
  Affymetrix HG U133A and Plus 2.0 array datasets with information on metastasis-free, disease-free or overall survival were accessed via public repositories. Time restricted Cox regression models were used to identify genes associated with metastasis during or after the first three years post-surgery (early- and late-type genes). A sequential validation study design, with two non-adjuvantly treated discovery cohorts (n = 409) and one validation cohort (n = 169) was applied and identified genes were further evaluated in tamoxifen-treated breast cancer patients (n = 923), as well as in patients with non-small cell lung (n = 1779), colon (n = 893) and ovarian (n = 922) cancer.
  
  
  RESULTS
  Ten late- and 243 early-type genes were identified in adjuvantly untreated breast cancer. Adjustment to clinicopathological factors and an established proliferation-related signature markedly reduced the number of early-type genes to 16, whereas nine late-type genes still remained significant. These nine genes were associated with metastasis-free survival (MFS) also in a non-time restricted model, but not in the early period alone, stressing that their prognostic impact was primarily based on MFS more than three years after surgery. Four of the ten late-type genes, the ribosome-related factors EIF4B, RPL5, RPL3, and the tumor angiogenesis modifier EPN3 were significantly associated with MFS in the late period also in a meta-analysis of tamoxifen-treated breast cancer cohorts. In contrast, only one late-type gene (EPN3) showed consistent survival associations in more than one cohort in the other cancer types, being associated with worse outcome in two non-small cell lung cancer cohorts. No late-type gene was validated in ovarian and colon cancer.
  
  
  CONCLUSIONS
  Ribosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients. In contrast, high expression of epsin (EPN3) was associated with increased risk of late metastasis. This is of clinical relevance considering the well-understood role of epsins in tumor angiogenesis and the ongoing development of epsin antagonizing therapies.
authors.affiliation: Department of Statistics, TU Dortmund University, Dortmund, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Hellwig
authors.affiliation: Department of Statistics, TU Dortmund University, Dortmund, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Madjar
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund University, Dortmund, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Edlund
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund University, Dortmund, Germany.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Marchan
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund University, Dortmund, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cadenas
authors.affiliation: Department of Obstetrics and Gynaecology, University Hospital, Mainz, Germany.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Heimes
authors.affiliation: Department of Obstetrics and Gynaecology, University Hospital, Mainz, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Almstedt
authors.affiliation: Department of Obstetrics and Gynaecology, University Hospital, Mainz, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Lebrecht
authors.affiliation: Department of Obstetrics and Gynaecology, University Hospital, Mainz, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Sicking
authors.affiliation: Department of Obstetrics and Gynaecology, University Hospital, Mainz, Germany.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Battista
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
authors.affiliation: Department of Obstetrics and Gynaecology, University Hospital, Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund University, Dortmund, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: Department of Statistics, TU Dortmund University, Dortmund, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Rahnenführer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000235:genetics*; D000090822:Ribosomal Protein L3; D012270:Ribosomes / Q000187:drug effects / Q000235:genetics*; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C434483:EPN3 protein, human; C000716547:RPL3 protein, human; D011960:Receptors, Estrogen; D000090822:Ribosomal Protein L3; D013629:Tamoxifen