title: MicroRNA-Related DNA Repair/Cell-Cycle Genes Independently Associated With Relapse After Radiation Therapy for Early Breast Cancer.
abstract: OBJECTIVE
  Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo.
  
  
  METHODS
  With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers--TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1--were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis.
  
  
  RESULTS
  We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy-treated patients but not in untreated matched control individuals (n=107; P<.05).
  
  
  CONCLUSIONS
  Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available.
authors.affiliation: The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia; Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia. Electronic address: harriet.gee@sydney.edu.au.
authors.forename: Harriet E
authors.initials: HE
authors.lastname: Gee
authors.affiliation: Department of Medical Oncology, The University of Oxford, Oxford, UK.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Department of Medical Oncology, The University of Oxford, Oxford, UK.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Toohey
authors.affiliation: The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Carroll
authors.affiliation: Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Cooper
authors.affiliation: The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia.
authors.forename: Jane
authors.initials: J
authors.lastname: Beith
authors.affiliation: The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia.
authors.forename: Catriona
authors.initials: C
authors.lastname: McNeil
authors.affiliation: The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia.
authors.forename: Hugh
authors.initials: H
authors.lastname: Carmalt
authors.affiliation: The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia.
authors.forename: Cindy
authors.initials: C
authors.lastname: Mak
authors.affiliation: The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Warrier
authors.affiliation: The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Holliday
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Selinger
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Beckers
authors.affiliation: Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Kennedy
authors.affiliation: Department of Radiation Oncology, Cancer Care Centre, St. George Hospital, Kogarah, NSW, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Graham
authors.affiliation: The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Kensington, NSW, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Swarbrick
authors.affiliation: The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Department of Anatomical Pathology, South Eastern Area Laboratory Service, St. George Hospital, Kogarah, NSW, Australia; School of Medicine and Health Sciences, University of Western Sydney, Campbelltown, NSW, Australia; Faculty of Medicine, School of Medical Sciences, University of NSW, Kensington, NSW, Australia.
authors.forename: Ewan K A
authors.initials: EK
authors.lastname: Millar
authors.affiliation: The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: O'Toole
authors.affiliation: The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Molloy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000532:radiotherapy*; D016022:Case-Control Studies; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018816:Genes, cdc; D005819:Genetic Markers; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011446:Prospective Studies; D011836:Radiation Tolerance / Q000235:genetics; D018714:Radiotherapy, Adjuvant; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D000097462:DNA Polymerase theta
chemical_list: D000951:Antigens, Neoplasm; D018931:Antineoplastic Agents, Hormonal; D004265:DNA Helicases; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D005819:Genetic Markers; D018398:Homeodomain Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D044786:S-Phase Kinase-Associated Proteins; D000097462:DNA Polymerase theta; C555098:MIRN139 microRNA, human; C064658:RAG-1 protein; C103532:RAD54L protein, human; C000618811:TOP2A protein, human