M K H Maus1, P P Grimminger2, P C Mack3, S H Astrow4, C Stephens4, G Zeger5, J Hsiang4, J Brabender2, M Friedrich6, H Alakus4, A H Hölscher2, P Lara7, K D Danenberg8, H J Lenz7, D R Gandara3. 1. Department of General, Visceral and Tumor Surgery, University of Cologne, Germany; Response Genetics, Inc., Los Angeles, CA, USA. Electronic address: mausman@gmx.at. 2. Response Genetics, Inc., Los Angeles, CA, USA. 3. Department of Molecular Biology and Biochemistry, University of California, Davis, Sacramento, USA. 4. Department of General, Visceral and Tumor Surgery, University of Cologne, Germany. 5. Department of General, Visceral and Tumor Surgery, University of Cologne, Germany; Department of Pathology, Keck School of Medicine, University of Southern California, USA. 6. Department of Thoracic, Vascular and Heart Surgery, University of Göttingen, Germany. 7. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA. 8. Formerly Response Genetics, Inc., Los Angeles, CA, USA.
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. 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.
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. 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.
Authors: David R Gandara; Philip C Mack; Carol Bult; Tianhong Li; Primo N Lara; Jonathan W Riess; Stephanie H Astrow; Regina Gandour-Edwards; David T Cooke; Ken Y Yoneda; Elizabeth H Moore; Chong-Xian Pan; Rebekah A Burich; Elizabeth A David; James G Keck; Susan Airhart; Neal Goodwin; Ralph W de Vere White; Edison T Liu Journal: Clin Lung Cancer Date: 2015-03-18 Impact factor: 4.785
Authors: Ahmet Yilmaz; Nehad Mohamed; Kara A Patterson; Yan Tang; Konstantin Shilo; Miguel A Villalona-Calero; Michael E Davis; Xiao-Ping Zhou; Wendy Frankel; Gregory A Otterson; Weiqiang Zhao Journal: Int J Environ Res Public Health Date: 2014-08-25 Impact factor: 3.390
Authors: Jaeyoung Cho; Sun Mi Choi; Jinwoo Lee; Chang-Hoon Lee; Sang-Min Lee; Dong-Wan Kim; Jae-Joon Yim; Young Tae Kim; Chul-Gyu Yoo; Young Whan Kim; Sung Koo Han; Young Sik Park Journal: Chin J Cancer Date: 2017-02-08