title: Comparative analysis of primary tumour and matched metastases in colorectal cancer patients: evaluation of concordance between genomic and transcriptional profiles.
abstract: OBJECTIVE
  Focal and temporal tumour heterogeneity can represent a major challenge for biology-guided therapies. This study proposes to investigative molecular discrepancies between primary colorectal cancer (CRC) samples and matched metastases.
  
  
  METHODS
  Surgical samples from primary and matched metastatic tissues from 13 CRC patients along with their adjacent normal tissue were evaluated. A mutational analysis was performed using a targeted Next Generation Sequencing assay (Foundation Medicine) with a focus on known recurrent somatic mutations as surrogate of key oncogenic events. Gene expression analysis was also performed to investigate transcriptional discrepancies.
  
  
  RESULTS
  Among the 26 samples, 191 mutations were identified including mutations in APC (13 pts), TP53 (11 pts), and KRAS (7 pts). Global concordance rate for mutations was 78% between primary and metastatic tumours and raised to 90% for 12 known recurrent mutations in CRC. Differential gene expression analysis revealed a low number of significantly variant transcripts between primary and metastatic tumours once the tissue effect was taken into account. Only two pathways (ST_ADRENERGIC, PID_REELINPATHWAY) were differentially up-regulated in metastases among 17 variant pathways. A common profile in primary and metastatic tumours revealed conserved pathways mostly involved in cell cycle regulation. Only two pathways were significantly down regulated compared to normal control, including regulation of autophagy (KEGG_REGULATION_OF_AUTOPHAGY).
  
  
  CONCLUSIONS
  These results suggest that profiles of primary tumour can identify key alterations present in matched CRC metastases at first metastatic progression. Gene expression analysis identified mainly conserved pathways between primary tumour and matched liver metastases.
authors: Oncologie Hématologie, Hôpitaux de Chartres, Chartres Le Coudray, France; INSERM U981, Gustave Roussy, Villejuif Grand Paris, France.
authors: Stéphane
authors: S
authors: Vignot
authors: INSERM U981, Gustave Roussy, Villejuif Grand Paris, France.
authors: Céline
authors: C
authors: Lefebvre
authors: Foundation Medicine, Cambridge, MA, USA.
authors: Garrett M
authors: GM
authors: Frampton
authors: Unité de Génomique Fonctionnelle, Gustave Roussy, Villejuif Grand Paris, France.
authors: Guillaume
authors: G
authors: Meurice
authors: Foundation Medicine, Cambridge, MA, USA.
authors: Roman
authors: R
authors: Yelensky
authors: Foundation Medicine, Cambridge, MA, USA.
authors: Gary
authors: G
authors: Palmer
authors: Groupe Hospitalier Pitié Salpêtrière, Paris, France.
authors: Frédérique
authors: F
authors: Capron
authors: Unité de Génomique Fonctionnelle, Gustave Roussy, Villejuif Grand Paris, France.
authors: Vladimir
authors: V
authors: Lazar
authors: Groupe Hospitalier Pitié Salpêtrière, Paris, France.
authors: Laurent
authors: L
authors: Hannoun
authors: Foundation Medicine, Cambridge, MA, USA.
authors: Vincent A
authors: VA
authors: Miller
authors: INSERM U981, Gustave Roussy, Villejuif Grand Paris, France.
authors: Fabrice
authors: F
authors: André
authors: Foundation Medicine, Cambridge, MA, USA.
authors: Philip J
authors: PJ
authors: Stephens
authors: INSERM U981, Gustave Roussy, Villejuif Grand Paris, France. Electronic address: jean-charles.soria@gustaveroussy.fr.
authors: Jean-Charles
authors: JC
authors: Soria
authors: Groupe Hospitalier Pitié Salpêtrière, Paris, France.
authors: Jean-Philippe
authors: JP
authors: Spano
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Colorectal cancer; Discrepancies; Metastasis; Primary tumour; Recurrent mutations