Between-region genetic divergence reflects the mode and tempo of tumor evolution.[2017][Nat Genet][10.1038_ng.3891]

《Between-region genetic divergence reflects the mode and tempo of tumor evolution.[2017][Nat Genet][10.1038_ng.3891]》由會員上傳分享，免費(fèi)在線閱讀，更多相關(guān)內(nèi)容在學(xué)術(shù)論文-天天文庫。

1、ArticlesBetween-regiongeneticdivergencereflectsthemodeandtempooftumorevolutionRupingSun1–3,9,ZhengHu1–3,9,AndreaSottoriva4,TrevorAGraham5,ArbelHarpak6,ZhichengMa1–3,JaredMFischer7,DarrylShibata8&ChristinaCurtis1–3Giventheimplicationsoftumordynamicsforprecisionmedicine,thereisane

2、edtosystematicallycharacterizethemodeofevolutionacrossdiversesolidtumortypes.Inparticular,methodstoinfertheroleofnaturalselectionwithinestablishedhumantumorsarelacking.Bysimulatingspatialtumorgrowthunderdifferentevolutionarymodesandexaminingpatternsofbetween-regionsubclonalgenet

3、icdivergencefrommultiregionsequencing(MRS)data,wedemonstratethatitisfeasibletodistinguishtumorsdrivenbystrongpositivesubclonalselectionfromthoseevolvingneutrallyorunderweakselection,asthelatterfailtodramaticallyaltersubclonalcomposition.Wedevelopedaclassifierbasedonmeasuresofbet

4、ween-regionsubclonalgeneticdivergenceandprojectedpatientdataintomodelspace,findingdifferentmodesofevolutionbothwithinandbetweensolidtumortypes.Ourfindingshavebroadimplicationsforhowhumantumorsprogress,howtheyaccumulateintratumoralheterogeneity,andultimatelyhowtheymaybemoreeffect

5、ivelytreated.Themultistagemodelofcarcinogenesisdescribedintheearly1950sexample,weproposedandtestedseveralpredictionsofaBigBang(refs.1,2)andNowell’s1976perspectivepieceontheclonalevolutionmodelofcolorectaltumorgrowth,wherein,aftertransformation,oftumorcells3providedaconceptualfra

6、meworkforunderstandingthetumorgrowsasasingleterminalexpansionpopulatedbyalargetumorprogression.Theseandotherstudies4,5werefoundationalinnumberofheterogeneous—andeffectivelyequallyfit—subclones15.definingtheelementsofsomaticevolution.However,theevolutionaryInthismodel,mostdetecta

7、blesubclonal(private)alterationsarisedynamicsthatgoverntumorinitiationandsubsequentgrowthafterearlyduringgrowth.Whilepost-transformationselectioncouldbetransformationremainpoorlyunderstood.Moreover,thedistinctiondetectedinthesecolorectaltumors,itwasoftentooweaktoalterbetweenstag

8、esisoftenblurredbecausetumorigenesisislargelyoc