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Review ARticle Introduction e molecular basis of lung cancer is complex and heterogenous. Improvements in our understanding of molecular alterations at multiple levels (genetic, epigenetic, protein expression) and their functional signicance have the potential to impact lung cancer diagnosis, prognostication and treatment. Lung cancers develop through a multistep process involving development of multiple genetic and epigenetic alterations, particularly activation of growth promoting pathways and inhibition of tumour suppressor pathways. Greater understanding of the multiple biochemical pathways involved in the molecular pathogenesis of lung cancer is crucial to the development of treatment strategies that can target molecular aberrations and their downstream activated pathways (1). Specific molecular alterations that drive tumour growth and provide targets for therapy have been best defined in adenocarcinomas (ADC) but there is increasing interest in the molecular landscape of squamous cell carcinoma (SCC) highlighting new potential therapeutic targets. In lung cancer as in other malignancies, tumourigenesis relates to activation of growth promoting proteins [e.g., v-Ki- ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), BRAF, MEK-1, HER2, MET, ALK and rearranged during transfection (RET)] as well as inactivation of tumour suppressor genes [e.g., P53, Molecular biology of lung cancer Wendy A. Cooper 1,2 , David C. L. Lam 3 , Sandra A. O’Toole 1,4,5 , John D. Minna 6 1 Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia; 2 School of Medicine, University of Western Sydney, NSW, Australia; 3 Department of Medicine, University of Hong Kong, Hong Kong SAR, China; 4 Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; 5 Sydney Medical School, University of Sydney, NSW, Australia; 6 Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, Texas, USA ABSTRACT Lung cancers are characterised by abundant genetic diversity with relatively few recurrent mutations occurring at high frequency. However, the genetic alterations often affect a common group of oncogenic signalling pathways. There have been vast improvements in our understanding of the molecular biology that underpins lung cancer in recent years and this has led to a revolution in the diagnosis and treatment of lung adenocarcinomas (ADC) based on the genotype of an individual’s tumour. New technologies are identifying key and potentially targetable genetic aberrations not only in adenocarcinoma but also in squamous cell carcinoma (SCC) of the lung. Lung cancer mutations have been identied in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KS), epidermal growth factor receptor (EGFR), BF and the parallel phosphatidylinositol 3-kinase (PI3K) pathway oncogenes and more recently in MEK and HER2 while structural rearrangements in ALK, ROS1 and possibly rearranged during transfection (RET) provide new therapeutic targets. Amplication is another mechanism of activation of oncogenes such as MET in adenocarcinoma, broblastgrowth factor receptor 1 (FGFR1) and discoidin domain receptor 2 (DDR2) in SCC. Intriguingly, many of these genetic alternations are associated with smoking status and with particular racial and gender dierences, which may provide insight into the mechanisms of carcinogenesis and role of host factors in lung cancer development and progression. e role of tumour suppressor genes is increasingly recognised with aberrations reported in TP53, PTEN, RB1, LKB11 and p16/CDKN2A. Identification of biologically significant genetic alterations in lung cancer that lead to activation of oncogenes and inactivation of tumour suppressor genes has the potential to provide further therapeutic opportunities. It is hoped that these discoveries may make a major contribution to improving outcome for patients with this poor prognosis disease. KEY WORDS Lung cancer; mutation; molecular pathology; oncogene; tumour suppressor gene J Thorac Dis 2013;5(S5):S479-S490. doi: 10.3978/j.issn.2072-1439.2013.08.03 Corresponding to: Associate Professor Wendy A. Cooper. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, Australia. Email: [email protected]. Submitted Jul 19, 2013. Accepted for publication Aug 01, 2013. Available at www.jthoracdis.com ISSN: 2072-1439 © Pioneer Bioscience Publishing Company. All rights reserved.

Molecular Biology of Lung Cancer

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! " # $ " %' ! ( $ ) * "!"#$%&'(#)%"Te molecular basis of lung cancer is complex and heterogenous. Improvementsinourunderstandingofmolecularalterationsat multiple levels (genetic, epigenetic, protein expression) and their functionalsignifcancehavethepotentialtoimpactlungcancer diagnosis,prognosticationandtreatment.Lungcancersdevelop throughamultistepprocessinvolvingdevelopmentofmultiple geneticandepigeneticalterations,particularlyactivation ofgrowthpromotingpathwaysandinhibitionoftumour suppressorpathways.Greaterunderstandingofthemultiple biochemical pathways involved in the molecular pathogenesis of lung cancer is crucial to the development of treatment strategies thatcantargetmolecularaberrationsandtheirdownstream activatedpathways(1).Specificmolecularalterationsthat drivetumourgrowthandprovidetargetsfortherapyhave beenbestdefinedinadenocarcinomas(ADC)butthereis increasinginterestinthemolecularlandscapeofsquamous cellcarcinoma(SCC)highlightingnewpotentialtherapeutic targets.Inlungcancerasinothermalignancies,tumourigenesis relatestoactivationofgrowthpromotingproteins[e!g.,v-Ki-ras2Kirstenratsarcomaviraloncogenehomolog(KRAS), epidermalgrowthfactorreceptor(EGFR),BRAF,MEK-1, HER2,MET,ALKandrearrangedduringtransfection(RET)] aswellasinactivationoftumoursuppressorgenes[e!g!"P53, *%+,('+-$ /)%+%01 %2 +'"0 (-"(,$Wendy A. Cooper1,2, Davld C. L. Lam3, Sandra A. O'Too|e1,4,5, [obn D. Mlnna61TlssuePatbo|ogyandDlagnostlcOnco|ogy,Poya|PrlnceA|lredHosplta|,Camperdown,Sydney,NSW,Austra|la, 2Scboo|olMedlclne, Unlverslty ol Western Sydney, NSW, Austra|la, 3Department ol Medlclne, Unlverslty ol Hong Kong, Hong Kong SAP, Cblna, 4Klngborn Cancer Centre and Garvan |nstltute ol Medlca| Pesearcb, Dar|lngburst, Sydney, NSW, Austra|la, 5Sydney Medlca| Scboo|, Unlverslty ol Sydney, NSW, Austra|la, 6Hamon Center lor Tberapeutlc Onco|ogy Pesearcb, Unlverslty ol Texas Soutbwestern Medlca| Center at Da||as, Texas, USA34567386Lungcancersarecharacterisedbyabundantgeneticdiversitywithrelativelyfewrecurrentmutationsoccurringathigh frequency.However,thegeneticalterationsoftenaffectacommongroupofoncogenicsignallingpathways.Therehave beenvastimprovementsinourunderstandingofthemolecularbiologythatunderpinslungcancerinrecentyearsand thishasledtoarevolutioninthediagnosisandtreatmentoflungadenocarcinomas(ADC)basedonthegenotypeof anindividualstumour.Newtechnologiesareidentifyingkeyandpotentiallytargetablegeneticaberrationsnotonlyin adenocarcinomabutalsoinsquamouscellcarcinoma(SCC)ofthelung.Lungcancermutationshavebeenidentifedin v-Ki-ras2Kirstenratsarcomaviraloncogenehomolog(KRS),epidermalgrowthfactorreceptor(EGFR),BRFandthe parallelphosphatidylinositol3-kinase(PI3K)pathwayoncogenesandmorerecentlyinMEKandHER2whilestructural rearrangementsinALK,ROS1andpossiblyrearrangedduringtransfection(RET)providenewtherapeutictargets. AmplifcationisanothermechanismofactivationofoncogenessuchasMETinadenocarcinoma,fbroblastgrowthfactor receptor1(FGFR1)anddiscoidindomainreceptor2(DDR2)inSCC.Intriguingly,manyofthesegeneticalternations areassociatedwithsmokingstatusandwithparticularracialandgenderdiferences,whichmayprovideinsightintothe mechanismsofcarcinogenesisandroleofhostfactorsinlungcancerdevelopmentandprogression.Teroleoftumour suppressorgenesisincreasinglyrecognisedwithaberrationsreportedinTP53,PTEN,RB1,LKB11andp16/CDKN2A. Identificationofbiologicallysignificantgeneticalterationsinlungcancerthatleadtoactivationofoncogenesand inactivation of tumour suppressor genes has the potential to provide further therapeutic opportunities. It is hoped that these discoveries may make a major contribution to improving outcome for patients with this poor prognosis disease. 9:; 5Lung cancer; mutation; molecular pathology; oncogene; tumour suppressor gene! #$%&'( )*+ ,-./012314536789368-: ;%*5 .-:/87:*++?:,-7,9.6/8:,-./:-HR8>9QR74 J-#OS-1Thep16INK4A/RBpathwayregulatescellcycleprogression fromG1toSphase.RB1isatumoursuppressorgenethat encodesRBproteinwhichregulatescellcycleG1/Stransition bybindingthetranscriptionfactorE2F1.RB1wasthefirst TSGdescribedinlungcancer(121)andisinactivatedin about90%ofsmallcelllungcarcinomasbutonlyabout 10-15%ofNSCLC(1).InNSCLC,thepathwayismostly switchedoffthroughalterationsofcyclinD1,CDK4andthe cyclindependentkinaseinhibitorp16(CDKN2A)(105). p16INK4AinhibitscyclinD1dependentphosphorylationofRB protein,therebypreventingcellcycletransitionthroughthe G1/Scheckpoint(122).p16INK4Aisinactivatedinabout80% ofNSCLC(123,124)andwasalteredin72%oflungSCCs examinedbyTCGA,mostlythroughhomozygousdeletion, methylationorinactivatingmutations(12).Inaddition,there isoverexpressionofcyclinD1throughgeneamplificationor other mechanisms in about 40% of NSCLC (123).*%+,('+-$ #-$0,#)"0 )" L58G8Thepresenceofthesemoleculartargetsasdescribedabovenow defnes the characteristics of NSCLC, with EGFR mutation and ALK rearrangements being the most clinically relevant at present (125). Teprevalenceofthesemutationsvariesinlungcancerarising frompatientindifferentregions(126).ActivatingEGFR mutationswerefoundinupto20%ofCaucasianswhileinthe AsianpopulationstheseEGFRmutationscanbepresentinup to40%ofpatientswithNSCLC(127).Teseethnicdiference inNSCLCpropertiesappearstobenotlimitedtothepresence ofactivatingEGFRmutationsbutisalsoevidentinotherdriver oncogenicmutationprofles(includingALK,KRS,METetc.), histologyandhencetumourresponsetotargetedtherapy treatment(63,126,128).Tepresenceofthesedrivermutations is generally found to be mutually exclusive to others in the same tumour (126). In lung ADC among Asians, ALK rearrangement isseeninupto7%ofpatientswithlungADC(79).Lung tumoursbearingEML4-ALKrearrangementarenon-responsive toconventionalchemotherapyorEGFR-tyrosinekinase inhibitors but are sensitive to a specifc tyrosine kinase inhibitor namedcrizotinib(129).Basedonourcurrentunderstandingof therapeuticmoleculartargetsofEGFRmutationandALKgene rearrangementinNSCLCandtheavailabilityofcorresponding targetedagents,analgorithmoftestingformoleculartargetsin NSCLCisproposedasinFigure1,whichrepresentsastepwise approachtotestingforindividualtargets,beginningwithEGFR then,ifnegative,ALKfusiongeneorotherpotentialtargetsif appropriate.AmongNSCLC,adenocarcinomaaccountsforupto80% ofhistologicalsubtypes(130).Therearepreviousreportsof correlations between histological subtypes of ADC demonstrating micropapillaryfeatureswithpresenceofactivatingEGFR mutations,leadingtothesuggestionsthatthepresenceof specificmutationsinNSCLCactuallyrepresentheterogeneity incancerbiologyandalsoresponsetotherapy(131).Giventhe heterogeneityoflungcancerhistology,however,histological subtypesaredifficulttobeusedasthesolereliablemarkerfor guidancetomolecularphenotypingandselectionoftargeted therapy (132,133).TargetingtherapeuticoncogenicmutationslikeEGFRand ALKcangivedramaticinitialtreatmentresponseoratleastan initial stable clinical disease. Te response rate is up to 70% in lung ADCbearingfavourableactivatingEGFRmutations(134).The median progression free survival is usually quoted as 9-11 months withdifferenttyrosinekinaseinhibitors(135,136),after whichmostpatientswithEGFRmutationswillexperience diseaseprogressionanddrugresistance.Aproportionofsuch drugresistanceisattributedtothedevelopmentofasecond mutation, usually T790M at exon 20 (137). It is hard to explain theeventuallossofdrugsensitivityintumoursbearingthose !""#$% $' ()* +")$,-)(% ,.(/0$1 2/ )-/0 ,(/,$% S486favourable EGFR mutations (exon 19 deletions and L858R) even withouttheacquisitionofsecondarymutationslikeT790M orthepresenceofotheruncommonorlessfavourableEGFR mutations.Thiscouldreflectsuboptimaltherapeutictargeting andbetterunderstandingonthebiologyofEGFR-related tumoursignallingandotheroncogenicmutationswillimprove drugtargetingandgivepatientsbeterpredictionoftherapeutic response and prognostication.8%"(+'I)%"ITheidentificationofdrivermutationsinEGFRandALK heraldedaneweraoftargetedtherapyinlungadenocarcinoma andadvancedsequencingtechnologiesareprovidingeven moresophisticatedinsightsintothemolecularaberrations inoncogenesandtumoursuppressorgenesunderlyinglung cancer(12,138-142).Thesestudieshaveidentifiedarangeof potentiallytargetablegeneticaberrationsinlungcancerbut havealsohighlightedatroublingcomplexityandheterogeneity whichposessignificantchallengesformoleculardiagnosisand targetedtreatment.Greaterknowledgeofthemolecularbiology andgenomiclandscapeoflungcancerofferspromiseforthe future.Improvementsinoutcomefromlungcancerwillalmost certainlyrequiretheidentificationofincreasingnumbersof everrarerdrivermutations,anddiagnosticapproachesthatcan identify multiple therapeutic targets ofer signifcant advantages. However,theidentificationofdrivergenomicaberrationsalso requirestheparalleldevelopmentofefectivetargetedtherapies andformanyofthesechanges(suchasKRAS)suchtherapies arenotyetavailable.Resistancetotargetedtherapeuticsisan increasinglyrecognisedissueintowhichgenomicanalyses mayprovideimportantmechanisticinsightsunderlyingfuture rational therapeutic approaches.3(T"%S+,&0,F,"#IFundingsources:SydneyFoundationforMedicalResearch; Hong Kong SK Yee Medical Foundation; Cancer Institute NSW ClinicalResearchFellowship10/1/07;SydneyBreastCancer Foundation;LifehouseatRoyalPrinceAlfredHospitalGrant; Lung Cancer SPORE P50CA70907. Disclosure:WChasreceivedhonorariafromPzerOncology. Figure1.Asuggestedalgorithmformoleculartargettestingbasedonunderstandingofrelevantmolecularbiologyinnon-smallcelllungcancer (NSCLC).Test for alterations in other molecular targets or pathways e.g. ALK, ROS1, RE1, cME1TtaTKI resistant mutatione.g. T790MECFR wildtypeTest for ECFR mutationsNSCLC, in particular adenocarcinomaBiomarker-based personalized therapy for lung cancerECFR mutantTKI responsive mutatione.g. exon 19 deletion, L858R, L861QEGFR TKI New generation EGFR- TKI Targeted therapy e.g. crizotinibe.g. AfatinibFurther research into presence of other biomarkers:1. To understand the molecular biology of lung cancer2. Feedback for clinical management +/- prognostication!"#$%&' ") *+"$&,-, .-/0&/01 2"' 31 4#55' 3 6,7"80$ 9:;< S487SOTisamemberoftheRocheAustraliaMolecularPathology AdvisoryBoard.Theauthorsdeclarenootherconflictsof interest7,2,$,"(,I1.LarsenJE, MinnaJD. Molecularbiologyoflungcancer:clinical implications. 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