1 Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan; 2 Department of Thoracic Surgery, Aichi Cancer Center, Japan; 3 Department of Thoracic Surgery, National Hospital Organization, Yamaguchi-Ube Medical Center, Japan. ABSTRACT P53 KRAS EGFR EGFR EGFR EGFR EML4-ALK EML4-ALK JJLC. KEY WORDS P53 KRAS EGFR EGFR EGFR EML4-ALK Japanese Journal of Lung Cancer
EGFR Figure1. Molecularpathogenesisoflungcancerbasedonhalmarksofcancer.Thisschemashowedtherelationship betweenhalmarksofcancerandmolecularalterationinlungcancer. Japanese Journal of Lung Cancer
Table1. GeneticAlterationandItsFrequency(%)inLungCancer Gene Chromosome Oncogene MYCL 1p34.2 MYCN 2p24.1 ALK 2p23 PIK3CA 3q26.3 ΔNP63 3q27-29 c-kit 4q11-12 FGFR4 5q35.3 EGFR/ERBB11 7p12 BRAF 7q34 MYCC 8q24 CCND1 11q13 KRAS 12p12 HER2/ERBB2 17q11 MET 7q31 Bcl-2 18q21 EML4-ALK 2p Tumorsuppressorgene LRP-DIT 2q21 FHIT 3p14.2 RASSF1A 3p21.3 NPRL2,BLU 3p21.3 FUS1,HYAL1 3p21.3 FUS2,SEMA3B 3p21.3 P16(INK4a) 9p21 P14(ARF) 9p21 PPP1R3 7q31 PTEN 10q23 DMBT1 10q25-26 100 PPP2R1B 11q23 TSLC1 11q23 P27KIP1 12p13 RB 13q14 P53 17q13 SMAD2 18q21 SMAD4 18q21 LKB1/STK11 19p13 Function transcriptionalfactor transcriptionalfactor receptortyrosinekinase PI3kinasesubunit P53homolog receptortyrosinekinase receptortyrosinekinase receptortyrosinekinase Ser/Thrkinase transcriptionalfactor celcyclemodulator GTPbindingprotein receptortyrosinekinase receptortyrosinekinase anti-apoptosis fusiontyrosinekinase lipoproteinreceptor dinucleotidetriphosphatase signaltransduction? cyclin-dependentkinaseinhibitor cyclin-dependentkinaseinhibitor Ser/Thrphosphatase tyrosinephosphatase Ser/Thrphosphatase adhesionmolecule celcycleregulator celcycleregulator TGF-βsignaltransduction TGF-βsignaltransduction Ser/Thrphosphatase Mechanism of alteration exp,amp exp,amp trans amp exp,amp,exp exp,amp exp,amp exp,amp, exp,amp, exp trans del del,me del,me del, 券献 del, 犬献 del, 鹸 del,,me me del, del me exp del, del, del, NSCLC <_50(squamous) (adeno) 50(adeno) 30 50 20(adeno) 25-60(adeno) 2-21 20 5(adeno) 40 40-70 30-40 <10 60 8 15 <10 15 85 70 20-30 60 <10 <10 10 SCLC 30 10 50 30 60 50-80 70-100 <10 10 40 80-100 80-100 NSCLC:non-smalcellungcancer,SCLC:smalcellungcancer,del:deletion,me:methylation,:ation,exp:alterationofexpression,amp:geneamplification,trans:translocation,adeno:adenocarcinoma. P53 KRAS LKB1 STK11 EGFR P16 RASSF1A β RARβ RAS Japanese Journal of Lung Cancer
EGFR EGFR EGFR EGFR EGFR HER2 EGFR HER2 MET MET MET MET MET PIK3CA α α PIK3CA AKT EGFR KRAS EGFR KRAS KRAS KRAS Japanese Journal of Lung Cancer
KRAS EGFR KRAS KRAS EGFR MEK1 EGFR KRAS BRAF MEK1 MYC FOS MYCC MYCL MYNC TITF1 TITF1 EGFR KRAS EGFR KRAS EML4-ALK EML4 ALK TRK KIF5B-ALK ALK EML4-ALK EML4 EML4-ALK EGFR KRAS EML4-ALK P53 RB P16 INK4a Japanese Journal of Lung Cancer
Figure2. Mutantalelespecificimbalance(MASI).Threemajorpaternsareobserved: 1)Balanced,havingaantalele(mA):wildtypealele(wA)ratio(mA/wA)ofabout1 withoutcopynumbergain(cng)(i.e.-masinotpresent);2)masibycng,eithercomplete(wa lost)orpartial(wa present);and3)uniparentaldisomy(upd;masiwithout CNG),duetocompletelossofwA andselectiveretention/duplicationofma,respectively. A fourthrarepatern,reversemasi,isdefinedaswildtypealelespecificimbalance. P16 INK4a P53 GADD45 P21 WAF1 Bax P53 AIP1 P53 P16 INK4a Japanese Journal of Lung Cancer
Figure3. CelcycleandRBandp53pathway. RASSF1 RAS RASSF1A FHIT γ α β γ γ γ Japanese Journal of Lung Cancer
Figure4. Modelsofmultistepmolecularalterationsintheprogressionoflungcancer.Accumulatingalterationofvari ousgenesresultsinclinicalyapparentlungcancer.ad,adenocarcinoma;sq,squamouscelcarcinoma;loh,lossof heterozygosity. KRAS P53 EGFR P16 INK4a EGFR EGFR EGFR EML4-ALK P53 EGFR KRAS P16 EGFR EML4-ALK EGFR EML4-ALK Japanese Journal of Lung Cancer
Figure5. p53and targetgenesofmicrorna-34s.the microrna-34sthatinhibitmultipleoncogenicgenesmediatestheprimaryfunctionofp53,celcyclearrestandinductionofapoptosisandsenescence. RAS c-myc P53 MET CDK4 c-myc Bcl-2 P53 TITF1 EGFR ERBB4 NTRK REFERENCES CA Cancer J Clin. Gen Thorac Cardiovasc Surg. Cancer Sci. N Engl J Med. Cell. Science. Japanese Journal of Lung Cancer
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