title: Heterogeneity in global gene expression profiles between biopsy specimens taken peri-surgically from primary ER-positive breast carcinomas.
abstract: BACKGROUND
  Gene expression is widely used for the characterisation of breast cancers. Variability due to tissue heterogeneity or measurement error or systematic change due to peri-surgical procedures can affect measurements but is poorly documented. We studied the variability of global gene expression between core-cuts of primary ER+ breast cancers and the impact of delays to tissue stabilisation due to sample X-ray and of diagnostic core cutting.
  
  
  METHODS
  Twenty-six paired core-cuts were taken immediately after tumour excision and up to 90 minutes delay due to sample X-ray; 57 paired core-cuts were taken at diagnosis and 2 weeks later at surgical excision. Whole genome expression analysis was conducted on extracted RNA. Correlations and differences were assessed between the expression of individual genes, gene sets/signatures and intrinsic subtypes.
  
  
  RESULTS
  Twenty-three and 56 sample pairs, respectively, were suitable for analysis. The range of correlations for both sample sets were similar with the majority being >0.97 in both. Correlations between pairs for 18 commonly studied genes were also similar between the studies and mainly with Pearson correlation coefficients >0.6 except for a small number of genes, which had a narrow-dynamic range (e.g. MKI67, SNAI2). There was no systematic difference in intrinsic subtyping between the first and second sample of either set but there was c.15 % discordance between the subtype assignments between the pairs, mainly where the subtyping of individual samples was less certain. Increases in the expression of several stress/early-response genes (e.g. FOS, FOSB, JUN) were found in both studies and confirmed findings in earlier smaller studies. Increased expression of IL6, IGFBP2 and MYC (by 17 %, 14 % and 44 %, respectively) occurred between the samples taken 2 weeks apart and again confirmed findings from an earlier study.
  
  
  CONCLUSIONS
  There is generally good correlation in gene expression between pairs of core-cuts except where genes have a narrow dynamic range. Similar correlation coefficients to the average gene expression profiles of intrinsic subtype, particularly LumA and LumB, can lead to discordances between assigned subtypes. Substantial changes in expression of early-response genes occur within an hour after surgery and in IL6, IGFB2 and MYC as a result of diagnostic core-cut biopsy.
  
  
  BACKGROUND
  Trial number CRUK/07/015 . Study start date September 2008.
authors.affiliation: Royal Marsden Hospital, London, UK. elena.lopez-knowles@icr.ac.uk.|Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK. elena.lopez-knowles@icr.ac.uk.
authors.forename: Elena
authors.initials: E
authors.lastname: López-Knowles
authors.affiliation: Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
authors.forename: Maggie Chon U
authors.initials: MC
authors.lastname: Cheang
authors.affiliation: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Morden
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Parker
authors.affiliation: Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Martin
authors.affiliation: Royal Marsden Hospital, London, UK.|Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK.|Present address: Kingston University, London, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pinhel
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: McNeill
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Hills
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Detre
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Afentakis
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Lila
authors.initials: L
authors.lastname: Zabaglo
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dodson
authors.affiliation: Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Skene
authors.affiliation: Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Holcombe
authors.affiliation: Faculty of Medicine & Health Sciences, Queen's Medical Centre, Nottingham, UK.
authors.forename: John
authors.initials: J
authors.lastname: Robertson
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.affiliation: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bliss
authors.affiliation: Royal Marsden Hospital, London, UK.|Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001706:Biopsy; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D059035:Perioperative Period; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; C508600:IL6 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D015850:Interleukin-6; D019394:Ki-67 Antigen; C489427:MYC protein, human; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc
keywords: Breast cancer; Gene expression; Heterogeneity