Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy

Pharmacogenomics J. 2015 Aug;15(4):354-62. doi: 10.1038/tpj.2014.73. Epub 2014 Dec 23.

Abstract

Colorectal cancer (CRC) is a heterogeneous disease with genetic profiles and clinical outcomes dependent on the anatomic location of the primary tumor. How location has an impact on the molecular makeup of a tumor and how prognostic and predictive biomarkers differ between proximal versus distal colon cancers is not well established. We investigated the associations between tumor location, KRAS and BRAF mutation status, and the messenger RNA (mRNA) expression of proteins involved in major signaling pathways, including tumor growth (epidermal growth factor receptor (EGFR)), angiogenesis (vascular endothelial growth factor receptor 2 (VEGFR2)), DNA repair (excision repair cross complement group 1 (ERCC1)) and fluoropyrimidine metabolism (thymidylate synthase (TS)). Formalin-fixed paraffin-embedded tumor specimens from 431 advanced CRC patients were analyzed. The presence of seven different KRAS base substitutions and the BRAF V600E mutation was determined. ERCC1, TS, EGFR and VEGFR2 mRNA expression levels were detected by reverse transcriptase-PCR. BRAF mutations were significantly more common in the proximal colon (P<0.001), whereas KRAS mutations occurred at similar frequencies throughout the colorectum. Rectal cancers had significantly higher ERCC1 and VEGFR2 mRNA levels compared with distal and proximal colon tumors (P=0.001), and increased TS levels compared with distal colon cancers (P=0.02). Mutant KRAS status was associated with lower ERCC1, TS, EGFR and VEGFR2 gene expression in multivariate analysis. In a subgroup analysis, this association remained significant for all genes in the proximal colon and for VEGFR2 expression in rectal cancers. The mRNA expression patterns of predictive and prognostic biomarkers, as well as associations with KRAS and BRAF mutation status depend on primary tumor location. Prospective studies are warranted to confirm these findings and determine the underlying mechanisms.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / genetics
  • Colonic Neoplasms / genetics
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • DNA-Binding Proteins / genetics
  • Drug Delivery Systems
  • Endonucleases / genetics
  • ErbB Receptors / genetics
  • Female
  • Gene Expression Profiling / methods*
  • Humans
  • Male
  • Middle Aged
  • Prognosis
  • Prospective Studies
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rectal Neoplasms / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / genetics

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • KRAS protein, human
  • RNA, Messenger
  • EGFR protein, human
  • ErbB Receptors
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • ERCC1 protein, human
  • Endonucleases
  • Proto-Oncogene Proteins p21(ras)