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

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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