Universität zu Köln

Maus, M. K. H., Hanna, D. L., Stephens, C. L., Astrow, S. H., Yang, D., Grimminger, P. P., Loupakis, F., Hsiang, J. H., Zeger, G., Wakatsuki, T., Barzi, A. and Lenz, H-J (2015). Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy. Pharmacogenomics J., 15 (4). S. 354 - 363. LONDON: NATURE PUBLISHING GROUP. ISSN 1473-1150

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Maus, M. K. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hanna, D. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stephens, C. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Astrow, S. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yang, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grimminger, P. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Loupakis, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hsiang, J. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeger, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wakatsuki, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Barzi, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lenz, H-J UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-398251
DOI:	10.1038/tpj.2014.73
Journal or Publication Title:	Pharmacogenomics J.
Volume:	15
Number:	4
Page Range:	S. 354 - 363
Date:	2015
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1473-1150
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language THYMIDYLATE SYNTHASE EXPRESSION; SIDED COLON-CANCER; ISLAND METHYLATOR PHENOTYPE; K-RAS MUTATIONS; PHASE-III TRIAL; MICROSATELLITE-INSTABILITY; 1ST-LINE TREATMENT; BRAF MUTATION; DIHYDROPYRIMIDINE DEHYDROGENASE; ADJUVANT CHEMOTHERAPY Multiple languages Genetics & Heredity; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39825