title: Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer.
abstract: OBJECTIVE
  A number of independent gene expression profiling studies have identified transcriptional subtypes in colorectal cancer with potential diagnostic utility, culminating in publication of a colorectal cancer Consensus Molecular Subtype classification. The worst prognostic subtype has been defined by genes associated with stem-like biology. Recently, it has been shown that the majority of genes associated with this poor prognostic group are stromal derived. We investigated the potential for tumor misclassification into multiple diagnostic subgroups based on tumoral region sampled.
  
  
  METHODS
  We performed multiregion tissue RNA extraction/transcriptomic analysis using colorectal-specific arrays on invasive front, central tumor, and lymph node regions selected from tissue samples from 25 colorectal cancer patients.
  
  
  RESULTS
  We identified a consensus 30-gene list, which represents the intratumoral heterogeneity within a cohort of primary colorectal cancer tumors. Using a series of online datasets, we showed that this gene list displays prognostic potential HR = 2.914 (confidence interval 0.9286-9.162) in stage II/III colorectal cancer patients, but in addition, we demonstrated that these genes are stromal derived, challenging the assumption that poor prognosis tumors with stem-like biology have undergone a widespread epithelial-mesenchymal transition. Most importantly, we showed that patients can be simultaneously classified into multiple diagnostically relevant subgroups based purely on the tumoral region analyzed.
  
  
  CONCLUSIONS
  Gene expression profiles derived from the nonmalignant stromal region can influence assignment of colorectal cancer transcriptional subtypes, questioning the current molecular classification dogma and highlighting the need to consider pathology sampling region and degree of stromal infiltration when employing transcription-based classifiers to underpin clinical decision making in colorectal cancer. Clin Cancer Res; 22(16); 4095-104. ©2016 AACRSee related commentary by Morris and Kopetz, p. 3989.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Dunne
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Darragh G
authors.initials: DG
authors.lastname: McArt
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Conor A
authors.initials: CA
authors.lastname: Bradley
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Paul G
authors.initials: PG
authors.lastname: O'Reilly
authors.affiliation: Department of Histopathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Barrett
authors.affiliation: Department of Histopathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Robert
authors.initials: R
authors.lastname: Cummins
authors.affiliation: Department of Histopathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Tony
authors.initials: T
authors.lastname: O'Grady
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Ken
authors.initials: K
authors.lastname: Arthur
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom. Department of Histopathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, United Kingdom.
authors.forename: Maurice B
authors.initials: MB
authors.lastname: Loughrey
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Allen
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Simon S
authors.initials: SS
authors.lastname: McDade
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Waugh
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hamilton
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.affiliation: Department of Histopathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Kay
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom. mark.lawler@qub.ac.uk.
authors.forename: Mark
authors.initials: M
authors.lastname: Lawler
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Sandra
authors.initials: S
authors.lastname: Van Schaeybroeck
mesh_terms: D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D009367:Neoplasm Staging; D009928:Organ Specificity / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor