title: Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy.
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.
authors.affiliation: 1] Department of General, Visceral and Tumor Surgery, University of Cologne, Cologne, Germany [2] Response Genetics, Inc., Los Angeles, CA, USA.
authors.forename: M K H
authors.initials: MK
authors.lastname: Maus
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Hanna
authors.affiliation: Response Genetics, Inc., Los Angeles, CA, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Stephens
authors.affiliation: Response Genetics, Inc., Los Angeles, CA, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Astrow
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of General, Visceral and Tumor Surgery, University of Cologne, Cologne, Germany.
authors.forename: P P
authors.initials: PP
authors.lastname: Grimminger
authors.affiliation: 1] Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA [2] Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Instituto Toscano, Tumori, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Response Genetics, Inc., Los Angeles, CA, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Hsiang
authors.affiliation: 1] Response Genetics, Inc., Los Angeles, CA, USA [2] Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zeger
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wakatsuki
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Barzi
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D016503:Drug Delivery Systems; D004720:Endonucleases / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C071447:ERCC1 protein, human; D004720:Endonucleases; D016283:Proto-Oncogene Proteins p21(ras)