Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

Publication date: 14 August 2017
Source:Cancer Cell, Volume 32, Issue 2
Author(s): The Cancer Genome Atlas Research NetworkBenjamin J.RaphaelRalph H.HrubanAndrew J.AguirreRichard A.MoffittJen JenYehChipStewartA. GordonRobertsonAndrew D.CherniackManaswiGuptaGadGetzStacey B.GabrielMatthewMeyersonCarrieCibulskisSuzanne S.FeiToshinoriHinoueHuiShenPeter W.LairdShiyunLingYilingLuGordon B.MillsRehanAkbaniPhillipeLoherEric R.LondinIsidoreRigoutsosAristeidis G.TelonisEwan A.GibbAnnaGoldenbergAziz M.MezliniKatherine A.HoadleyEricCollissonEricLanderBradley A.MurrayJulianHessMaraRosenbergLouisBergelsonHaileiZhangJuokChoGraceTiaoJaegilKimDimitriLivitzIgnatyLeshchinerBrendanReardonEliezerVan AllenAtanasKamburovRameenBeroukhimGordonSaksenaSteven E.SchumacherMichael S.NobleDavid I.HeimanNilsGehlenborgJaegilKimMichael S.LawrenceVolkanAdsayGloriaPetersenDavidKlimstraNabeelBardeesyMark D.M.LeisersonReanneBowlbyKatayoonKasaianInancBirolKaren L.MungallSaraSadeghiJohn N.WeinsteinPaul T.SpellmanYuexinLiuLaufey T.AmundadottirJoelTepperAatur D.SinghiRajivDhirDrwiegaPaulThomasSmyrkLizhiZhangPaulaKimJayBowenJessicaFrickJulie M.Gastier-FosterMarkGerkenKevinLauKristen M.LeraasTara M.LichtenbergNilsa C.RamirezJeremyRenkelMarkShermanLisaWisePeggyYenaErikZmudaJuliannShihAdrianAllyMirunaBalasundaramRebeccaCarlsenAndyChuEricChuahAmandaClarkeNoreenDhallaRobert A.HoltSteven J.M.JonesDarleneLeeYussanneMaMarco A.MarraMichaelMayoRichard A.MooreAndrew J.MungallJacqueline E.ScheinPayalSipahimalaniAngelaTamNinaThiessenKaneTseTinaWongDeniseBrooksJ. ToddAumanSaianandBaluTomBodenheimerD. NeilHayesAlan P.HoyleStuart R.JefferysCorbin D.JonesShaowuMengPiotr A.MieczkowskiLisle E.MoseCharles M.PerouAmy H.PerouJeffreyRoachYanShiJanae V.SimonsTaraSkellyMatthew G.SolowayDonghuiTanUmadeviVeluvoluJoel S.ParkerMatthew D.WilkersonAnilKorkutYasinSenbabaogluPatrickBurchRobertMcWilliamsKariChaffeeAnnObergWeiZhangMarie-ClaudeGingrasDavid A.WheelerLiuXiMoniqueAlbertJohnBartlettHarmanSekhonYeagerStephenZarenHowardMillerJudyAnneBreggiaRachna T.ShroffSudhaChudamaniJiaLiuLaxmiLollaRashiNareshToddPihlQiangSunYunhuWanYeWuSmithJenniferKevinRogginKarl-FriedrichBeckerMadhusmitaBeheraJosephBennettLoriBoiceEricBurksCarlos GilbertoCarlotti JuniorJohnChabotDanielaPretti da Cunha TirapelliJoseSebastião dos SantosMichaelDubinaJenniferEschbacherMeiHuangLoriHuelsenbeck-DillRogerJenkinsAlexeyKarpovRafaelKempVladimirLyadovShishirMaithelGeorgyManikhasEricMontgomeryHoutanNoushmehrAdeboyeOsunkoyaTaofeekOwonikokoOxanaPaklinaOlgaPotapovaSureshRamalingamW. KimrynRathmellKimberlyRieger-ChristCharlesSallerGaliyaSetdikovaAlexeyShabuninGabrielSicaTaoSuTravisSullivanPatSwansonKatherineTarvinMichaelTavobilovLeigh B.ThorneStefanUrbanskiOlgaVoroninaTimothyWangDanielCrainErinCurleyJohannaGardnerDavidMalleryScottMorrisJosephPaulauskisRobertPennyCandaceSheltonTroySheltonKlaus-PeterJanssenOliverBatheNathanBaharyJuliaSlotta-HuspeninaAmberJohnsHaninaHibshooshRosa F.HwangAntoniaSepulvedaAmieRadenbaughStephen B.BaylinMarioBerriosMoiz S.BootwallaAndreaHolbrookPhillip H.LaiDennis T.MaglinteSwapnaMahurkarTimothy J.TricheJr.David J.Van Den BergDaniel J.WeisenbergerLyndaChinRajuKucherlapatiMelanieKucherlapatiAngelikiPantaziPeterParkGordonSaksenaDougVoetPeiLinScottFrazerTimothyDefreitasSamMeierLyndaChinSun YoungKwonYong HoonKimSang-JaeParkSung-SikHanSeong HoonKimHarkKimEmmaFurthMargaretTemperoChrisSanderAndrewBiankinDavidChangPeterBaileyAnthonyGillJamesKenchSeanGrimmondAmberJohnsAustralian PancreaticCancer Genome Initiative (APGIRussellPostierRosemaryZunaHuguesSicotteJohn A.DemchokMartin L.FergusonCarolyn M.HutterKenna R.Mills ShawMargiShethHeidi J.SofiaRoyTarnuzzerZhiningWangLimingYangJiashan (Julia)ZhangInaFelauJean C.Zenklusen
We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

Graphical abstract

Teaser

This TCGA study reveals the complex molecular landscape of PDAC, with a small number of tumors carrying multiple KRAS mutations, KRAS wild-type PDACs harboring alterations in other RAS pathway genes or alternate oncogenic drivers, and integrated RNA and protein subtypes indicating clinically significant subsets of disease.


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