title: KRAS mutations in non-small-cell lung cancer and colorectal cancer: implications for EGFR-targeted therapies.
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 wild-type (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.
  
  
  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%).
  
  
  CONCLUSIONS
  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.
authors: Department of General, Visceral and Tumor Surgery, University of Cologne, Germany; Response Genetics, Inc., Los Angeles, CA, USA. Electronic address: mausman@gmx.at.
authors: M K H
authors: MK
authors: Maus
authors: Response Genetics, Inc., Los Angeles, CA, USA.
authors: P P
authors: PP
authors: Grimminger
authors: Department of Molecular Biology and Biochemistry, University of California, Davis, Sacramento, USA.
authors: P C
authors: PC
authors: Mack
authors: Department of General, Visceral and Tumor Surgery, University of Cologne, Germany.
authors: S H
authors: SH
authors: Astrow
authors: Department of General, Visceral and Tumor Surgery, University of Cologne, Germany.
authors: C
authors: C
authors: Stephens
authors: Department of General, Visceral and Tumor Surgery, University of Cologne, Germany; Department of Pathology, Keck School of Medicine, University of Southern California, USA.
authors: G
authors: G
authors: Zeger
authors: Department of General, Visceral and Tumor Surgery, University of Cologne, Germany.
authors: J
authors: J
authors: Hsiang
authors: Response Genetics, Inc., Los Angeles, CA, USA.
authors: J
authors: J
authors: Brabender
authors: Department of Thoracic, Vascular and Heart Surgery, University of Göttingen, Germany.
authors: M
authors: M
authors: Friedrich
authors: Department of General, Visceral and Tumor Surgery, University of Cologne, Germany.
authors: H
authors: H
authors: Alakus
authors: Response Genetics, Inc., Los Angeles, CA, USA.
authors: A H
authors: AH
authors: Hölscher
authors: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
authors: P
authors: P
authors: Lara
authors: Formerly Response Genetics, Inc., Los Angeles, CA, USA.
authors: K D
authors: KD
authors: Danenberg
authors: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
authors: H J
authors: HJ
authors: Lenz
authors: Department of Molecular Biology and Biochemistry, University of California, Davis, Sacramento, USA.
authors: D R
authors: DR
authors: Gandara
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D063646:Carcinogenesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000628:therapy; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000628:therapy; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000276:immunology; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000628:therapy; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012907:Smoking / Q000009:adverse effects / Q000235:genetics; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Colorectal cancer (CRC); EGFR-targeted therapy; KRAS mutations; Molecular genetics; Non-small-cell lung cancer (NSCLC); Personalized medicine; Predictive biomarkers