title: A systematic review and meta-analysis of somatic and germline DNA sequence biomarkers of esophageal cancer survival, therapy response and stage.
abstract: BACKGROUND
  There is an urgent need for biomarkers to help predict prognosis and guide management of esophageal cancer. This review identifies, evaluates and meta-analyses the evidence for reported somatic and germline DNA sequence biomarkers of outcome and stage.
  
  
  METHODS
  A systematic review was carried out of the PubMed, EMBASE and Cochrane databases (20 August 2014), in conjunction with the ASCO Level of Evidence scale for biomarker research. Meta-analyses were carried out for all reported markers associated with outcome measures by more than one study.
  
  
  RESULTS
  Four thousand and four articles were identified, 762 retrieved and 182 studies included. There were 65 reported markers of survival or recurrence 12 (18.5%) were excluded due to multiple comparisons. Following meta-analysis, significant associations were seen for six tumor variants (mutant TP53 and PIK3CA, copy number gain of ERBB2/HER2, CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms: ERCC1 rs3212986, ERCC2 rs1799793, TP53 rs1042522, MDM2 rs2279744, TYMS rs34743033, ABCB1 rs1045642 and MTHFR rs1801133. Twelve germline markers of treatment complications were reported; 10 were excluded. Two tumor and 15 germline markers (11 excluded) of chemo (radio)therapy response were reported. Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487. There were 41 tumor/germline reported markers of stage; 27 (65.9%) were excluded.
  
  
  CONCLUSIONS
  Numerous DNA markers of outcome and stage have been reported, yet few are backed by high-quality evidence. Despite this, a small number of variants appear reliable. These merit evaluation in prospective trials, within the context of high-throughput sequencing and gene expression.
authors.affiliation: Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; Oxford OesophagoGastric Centre.
authors.forename: J M
authors.initials: JM
authors.lastname: Findlay
authors.affiliation: NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK. Electronic address: jfindlay@well.ox.ac.uk.
authors.forename: I
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000628:therapy; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm
keywords: biomarkers; cancer; cancer staging; esophageal; genomic; prognosis