Universität zu Köln

Maus, M. K. H., Grimminger, P. P., Mack, P. C., Astrow, S. H., Stephens, C., Zeger, G., Hsiang, J., Brabender, J., Friedrich, M., Alakus, H., Hoelscher, A. H., Lara, P., Danenberg, K. D., Lenz, H. J. and Gandara, D. R. (2014). KRAS mutations in non-small-cell lung cancer and colorectal cancer: Implications for EGFR-targeted therapies. Lung Cancer, 83 (2). S. 163 - 168. CLARE: ELSEVIER IRELAND LTD. ISSN 1872-8332

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Abstract

Background: KRAS mutations are associated with diverse biologic functions as well as prognostic and predictive impact in non-small cell-lung cancer (NSCLC) and colorectal cancer (CRC). In CRC, benefit from monoclonal antibody therapies targeting EGFR is generally limited to patients whose tumors have wildtype (WT) KRAS, whereas data suggest that this association is not present for NSCLC. We hypothesized that the unique tobacco-related carcinogenesis of NSCLC results in a divergence of KRAS MT genotype compared with CRC, contributing to differences in outcomes from EGFR-targeted therapies. Material and methods: Tumor from 2603 patients (838 CRC and 1765 NSCLC) was analyzed for KRAS mutations. DNA was extracted from microdissected formalin-fixed-paraffin-embedded specimens (FFPE) and 7 different base substitutions in codons 12 and 13 of KRAS were determined. Results: KRAS mutation genotype differed significantly between NSCLC and CRC in frequency (25% vs. 39%; p<0.001), smoking-associated G>T transversions (73% versus 27%; p<0.001), and ratio of transversions to transitions (3.5 vs. 0.79; p<0.001). In NSCLC GLY12Cys mutations, resulting from a codon 12 GGT>TGT substitution, were observed in 44% compared to 10% for CRC. In contrast, codon 12 or 13 GLY>ASP substitutions (resulting in a G>A transition) were more frequent in CRC (42%) compared with NSCLC (21%). Conclusion: In this large dataset, KRAS mutation patterns are quantitatively and qualitatively distinct between NSCLC and CRC, reflecting in part differences in tobacco-related carcinogenesis. In light of differences in predictive value for EGFR-directed monoclonal antibody therapy and prognosis for specific KRAS mutations between NSCLC and CRC, these data provide an underlying biologic rationale. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Maus, M. K. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grimminger, P. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mack, P. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Astrow, S. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stephens, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeger, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hsiang, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brabender, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Friedrich, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alakus, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelscher, A. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lara, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Danenberg, K. D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lenz, H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gandara, D. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-447720
DOI:	10.1016/j.lungcan.2013.11.010
Journal or Publication Title:	Lung Cancer
Volume:	83
Number:	2
Page Range:	S. 163 - 168
Date:	2014
Publisher:	ELSEVIER IRELAND LTD
Place of Publication:	CLARE
ISSN:	1872-8332
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language K-RAS MUTATIONS; GROWTH-FACTOR RECEPTOR; ONCOLOGY-GROUP; CETUXIMAB; CHEMOTHERAPY; METAANALYSIS; TRIAL; ONCOGENE; EFFICACY; BEHAVIOR Multiple languages Oncology; Respiratory System Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44772