title: Discovery and validation of molecular biomarkers for colorectal adenomas and cancer with application to blood testing.
abstract: OBJECTIVE
  Colorectal cancer incidence and deaths are reduced by the detection and removal of early-stage, treatable neoplasia but we lack proven biomarkers sensitive for both cancer and pre-invasive adenomas. The aims of this study were to determine if adenomas and cancers exhibit characteristic patterns of biomarker expression and to explore whether a tissue-discovered (and validated) biomarker is differentially expressed in the plasma of patients with colorectal adenomas or cancer.
  
  
  METHODS
  Candidate RNA biomarkers were identified by oligonucleotide microarray analysis of colorectal specimens (222 normal, 29 adenoma, 161 adenocarcinoma and 50 colitis) and validated in a previously untested cohort of 68 colorectal specimens using a custom-designed oligonucleotide microarray. One validated biomarker, KIAA1199, was assayed using qRT-PCR on plasma extracted RNA from 20 colonoscopy-confirmed healthy controls, 20 patients with adenoma, and 20 with cancer.
  
  
  RESULTS
  Genome-wide analysis uncovered reproducible gene expression signatures for both adenomas and cancers compared to controls. 386/489 (79%) of the adenoma and 439/529 (83%) of the adenocarcinoma biomarkers were validated in independent tissues. We also identified genes differentially expressed in adenomas compared to cancer. KIAA1199 was selected for further analysis based on consistent up-regulation in neoplasia, previous studies and its interest as an uncharacterized gene. Plasma KIAA1199 RNA levels were significantly higher in patients with either cancer or adenoma (31/40) compared to neoplasia-free controls (6/20).
  
  
  CONCLUSIONS
  Colorectal neoplasia exhibits characteristic patterns of gene expression. KIAA1199 is differentially expressed in neoplastic tissues and KIAA1199 transcripts are more abundant in the plasma of patients with either cancer or adenoma compared to controls.
authors.affiliation: Flinders Centre for Cancer Prevention and Control, Flinders University of South Australia, Adelaide, South Australia, Australia. larry.lapointe@flinders.edu.au
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: LaPointe
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Pedersen
authors.forename: Robert
authors.initials: R
authors.lastname: Dunne
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Brown
authors.forename: Letitia
authors.initials: L
authors.lastname: Pimlott
authors.forename: Snigdha
authors.initials: S
authors.lastname: Gaur
authors.forename: Aidan
authors.initials: A
authors.lastname: McEvoy
authors.forename: Melissa
authors.initials: M
authors.lastname: Thomas
authors.forename: David
authors.initials: D
authors.lastname: Wattchow
authors.forename: Peter L
authors.initials: PL
authors.lastname: Molloy
authors.forename: Graeme P
authors.initials: GP
authors.lastname: Young
mesh_terms: D000236:Adenoma / Q000097:blood* / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006821:Hyaluronoglucosaminidase; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D011506:Proteins; C491433:CEMIP protein, human; D006821:Hyaluronoglucosaminidase