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KRAS oncogene substitutions in Korean NSCLC patients: Clinical implication and relationship with pAKT and RalGTPases expression

 Eun Young Kim  ;  Arum Kim  ;  Se Kyu Kim  ;  Hyung Jung Kim  ;  Joon Chang  ;  Chul Min Ahn  ;  Jae Seok Lee  ;  Hyo Sup Shim  ;  Yoon Soo Chang 
 LUNG CANCER, Vol.85(2) : 299-305, 2014 
Journal Title
Issue Date
Aged ; Aged, 80 and over ; Amino Acid Substitution ; Carcinoma, Non-Small-Cell Lung/genetics* ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Codon ; DNA Mutational Analysis ; Female ; Gene Expression ; Genes, ras* ; Humans ; Immunohistochemistry ; Lung Neoplasms/genetics* ; Lung Neoplasms/metabolism ; Lung Neoplasms/mortality ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Mutation* ; Neoplasm Staging ; Proto-Oncogene Proteins c-akt/metabolism ; Republic of Korea ; Retrospective Studies ; Risk Factors ; ral GTP-Binding Proteins/genetics ; ral GTP-Binding Proteins/metabolism
KRAS ; NSCLC ; RalA ; RalB ; RalGTPases ; pAKT
OBJECTIVES: Since different conformation of each KRAS mutant leads to inherent downstream signaling, its distribution, influence on the clinical outcome, and effect on the signaling mediators were investigated in the Korean NSCLC patients whose tumor have KRAS mutation.
MATERIALS AND METHODS: Mutation at KRAS codons 12 and 13 was evaluated in 1420 Korean NSCLC by direct sequencing and expression of RalA, RalB, and pAKT-Ser473 was evaluated by immunohistochemistry in 30 cases whose KRAS mutant tumor tissues were available.
RESULTS: Eighty-two (5.8%) out of 1420 patients harbored a KRAS mutation either in codon 12 or 13. Gly12Asp was the most frequent (34.1%), followed by Gly12Cys (22.0%) and Gly12Val (13.4%). Transversion at codons 12 and 13, which includes Gly12Cys, Gly12Val, Gly12Ala, Gly13Cys, and Gly12Phe was detected in 45 cases (54.9%) and transition, including Gly12Asp, Gly12Ser, and Gly13Asp was detected in 37 cases (45.1%). Male and smoking history were associated with transversion (p=0.001 and 0.006, respectively; χ(2)-test), and multivariate analysis showed that gender was an independent influencing factor (p=0.026; Cochran-Mantel-Haenszel test). Multivariate analysis on survival revealed that KRAS mutation subtype did not influence overall survival of the patients with KRAS mutations after adjustment for age, gender, performance status, and stage. There were no differences in the nuclear and cytoplasmic expression of pAKT-Ser473 between transversion and transition mutants. Expression of Ral-GTPases, RalA and RalB, did not differ between transversion and transition mutants, however, strong expression of RalB in the tissue of patients with KRAS mutants was associated with advanced stages (P-value=0.020, χ(2)-test).
CONCLUSIONS: In this study population, not only the frequency of KRAS mutation but also the distribution of its subtypes differed from those of Western studies, with unique influencing factors. Clinical outcome and expression of pAKT-Ser473, RalA, and RalB did not differ among subtypes.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Medical Education (의학교육학과) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Se Kyu(김세규)
Kim, Arum(김아름)
Kim, Eun Young(김은영) ORCID logo https://orcid.org/0000-0002-3281-5744
Kim, Hyung Jung(김형중) ORCID logo https://orcid.org/0000-0003-2498-0683
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
Ahn, Chul Min(안철민)
Lee, Jae Seok(이재석)
Chang, Yoon Soo(장윤수) ORCID logo https://orcid.org/0000-0003-3340-4223
Chang, Joon(장준) ORCID logo https://orcid.org/0000-0003-4542-6841
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