Number and Size Distribution of Colorectal Adenomas under the Multistage Clonal Expansion Model of Cancer 英文参考文献.docVIP

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Number and Size Distribution of Colorectal Adenomas under the Multistage Clonal Expansion Model of Cancer 英文参考文献.doc

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Number and Size Distribution of Colorectal Adenomas under the Multistage Clonal Expansion Model of Cancer 英文参考文献

NumberandSizeDistributionofColorectalAdenomas undertheMultistageClonalExpansionModelofCancer AnupDewanji1,JihyounJeon2,RafaelMeza2,3,E.GeorgLuebeck4* 1AppliedStatisticsDivision,IndianStatisticalInstitute,Kolkata,India,2PrograminBiostatisticsandBiomathematics,FredHutchinsonCancerResearchCenter,Seattle, Washington, United States of America, 3Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America, 4Program in ComputationalBiology,FredHutchinsonCancerResearchCenter,Seattle,Washington,UnitedStatesofAmerica Abstract Colorectal cancer (CRC) is believed to arise from mutant stem cells in colonic crypts that undergo a well-characterized progression involving benign adenoma, the precursor to invasive carcinoma. Although a number of (epi)genetic events havebeenidentifiedasdriversofthisprocess,littleisknownaboutthedynamicsinvolvedinthestage-wiseprogression fromthefirstappearanceofanadenomatoitsultimateconversiontomalignantcancer.Bythetimeadenomasbecome endoscopicallydetectable(i.e.,areintherangeof1–2mmindiameter),adenomasarealreadycomprisedofhundredsof thousandsofcellsandmayhavebeeninexistenceforseveralyearsifnotdecades.Thus,alargefractionofadenomasmay actuallyremainundetectedduringendoscopicscreeningand,atleastinprinciple,couldgiverisetocancerbeforetheyare detected.Itisthereforeofimportancetoestablishwhatfractionofadenomasisdetectable,bothasafunctionofwhenthe colon is screened for neoplasia and as a function of the achievable detection limit. To this end, we have derived mathematical expressions for the detectable adenoma number and size distributions based on a recently developed stochasticmodelofCRC.Ourresultsandillustrationsusingtheseexpressionssuggest(1)thatscreeningefficacyiscritically dependentonthedetectionthresholdandimplicitknowledgeoftherelevantstemcellfractioninadenomas,(2)thata largefractionofnon-extinctadenomasremainslikelyundetectedassumingplausibledetectionthresholdsandcelldivision rates,and(3),underarealisticdescript