title: Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.
abstract: BACKGROUND
  Differences exist between the proximal and distal colon in terms of developmental origin, exposure to patterning genes, environmental mutagens, and gut flora. Little is known on how these differences may affect mechanisms of tumorigenesis, side-specific therapy response or prognosis. We explored systematic differences in pathway activation and their clinical implications.
  
  
  METHODS
  Detailed clinicopathological data for 3045 colon carcinoma patients enrolled in the PETACC3 adjuvant chemotherapy trial were available for analysis. A subset of 1404 samples had molecular data, including gene expression and DNA copy number profiles for 589 and 199 samples, respectively. In addition, 413 colon adenocarcinoma from TCGA collection were also analyzed. Tumor side-effect on anti-epidermal growth factor receptor (EGFR) therapy was assessed in a cohort of 325 metastatic patients. Outcome variables considered were relapse-free survival and survival after relapse (SAR).
  
  
  RESULTS
  Proximal carcinomas were more often mucinous, microsatellite instable (MSI)-high, mutated in key tumorigenic pathways, expressed a B-Raf proto-oncogene, serine/threonine kinase (BRAF)-like and a serrated pathway signature, regardless of histological type. Distal carcinomas were more often chromosome instable and EGFR or human epidermal growth factor receptor 2 (HER2) amplified, and more frequently overexpressed epiregulin. While risk of relapse was not different per side, SAR was much poorer for proximal than for distal stage III carcinomas in a multivariable model including BRAF mutation status [N = 285; HR 1.95, 95% CI (1.6-2.4), P < 0.001]. Only patients with metastases from a distal carcinoma responded to anti-EGFR therapy, in line with the predictions of our pathway enrichment analysis.
  
  
  CONCLUSIONS
  Colorectal carcinoma side is associated with differences in key molecular features, some immediately druggable, with important prognostic effects which are maintained in metastatic lesions. Although within side significant molecular heterogeneity remains, our findings justify stratification of patients by side for retrospective and prospective analyses of drug efficacy and prognosis.
authors: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: E
authors: E
authors: Missiaglia
authors: Molecular Digestive Oncology Unit, University Hospital Leuven, Leuven, Belgium.
authors: B
authors: B
authors: Jacobs
authors: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: G
authors: G
authors: D'Ario
authors: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: A F
authors: AF
authors: Di Narzo
authors: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: C
authors: C
authors: Soneson
authors: Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic.
authors: E
authors: E
authors: Budinska
authors: Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic.
authors: V
authors: V
authors: Popovici
authors: Molecular Digestive Oncology Unit, University Hospital Leuven, Leuven, Belgium.
authors: L
authors: L
authors: Vecchione
authors: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: S
authors: S
authors: Gerster
authors: Department of Pathology, Lausanne University, Lausanne.
authors: P
authors: P
authors: Yan
authors: Oncosurgery Unit, Geneva University Hospital, Geneva.
authors: A D
authors: AD
authors: Roth
authors: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; The Swiss Group for Clinical Cancer Research (SAKK) Coordinating Center, Bern.
authors: D
authors: D
authors: Klingbiel
authors: Department of Pathology, Lausanne University, Lausanne.
authors: F T
authors: FT
authors: Bosman
authors: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; Ludwig Center for Cancer Research; Oncology Department, University of Lausanne, Lausanne, Switzerland.
authors: M
authors: M
authors: Delorenzi
authors: Molecular Digestive Oncology Unit, University Hospital Leuven, Leuven, Belgium. Electronic address: sabine.tejpar@uzleuven.be.
authors: S
authors: S
authors: Tejpar
mesh_terms: D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D057170:Translational Research, Biomedical
chemical_list: C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas
keywords: colon cancer; expression profiling; mutations; oncogenic pathways; survival