title: KRAS oncogene substitutions in Korean NSCLC patients: clinical implication and relationship with pAKT and RalGTPases expression.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Biomedical Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Arum
authors.initials: A
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Se Kyu
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyung Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chul Min
authors.initials: CM
authors.lastname: Ahn
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyo Sup
authors.initials: HS
authors.lastname: Shim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: yschang@yuhs.ac.
authors.forename: Yoon Soo
authors.initials: YS
authors.lastname: Chang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003062:Codon; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D056910:Republic of Korea; D012189:Retrospective Studies; D012307:Risk Factors; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D003062:Codon; D051057:Proto-Oncogene Proteins c-akt; D020725:ral GTP-Binding Proteins
keywords: KRAS; NSCLC; RalA; RalB; RalGTPases; pAKT