基于149个候选基因上胚系罕见变异的中国人群癌症遗传病因研究

基于149个候选基因上胚系罕见变异的中国人群癌症遗传病因研究基于149个候选基因上胚系罕见变异的中国人群癌症遗传病因研究

摘要:

胚系罕见变异（raregermlinevariants,RGVar）是导致遗传疾病的主要因素之一，也是癌症遗传病因的重要组成部分。本研究旨在通过对中国人群癌症家系中149个候选基因进行全外显子测序，分析胚系RGVar与癌症遗传病因的关联性。本研究共纳入来自不同类型癌症家系的58个患者样本及其家系成员，年龄分布23-80岁，男女比例接近1:1。我们筛选出133个RGVar，包括92个突变和41个DNA重复/缺失/插入变异，其中48个被确认为致病性变异。这些变异主要涉及DNA修复、细胞周期调控和信号转导等关键基因的失控或突变，与癌症遗传病因密切相关。进一步的功能和基因通路分析表明，RGVar在多种癌症中均起着重要作用，包括结直肠癌、胃癌、乳腺癌和肺癌等。在癌症家系中，胚系RGVar并不局限于患者本身，而是广泛分布于家系中的其他成员，提示了家族遗传风险的可能性。综上，本研究通过全外显子测序法鉴定了多个与癌症遗传病因密切相关的胚系RGVar，为家族性癌症的遗传机制提供了新的证据和参考。

关键词:RGVar、全外显子测序、癌症、遗传病因、多基因疾病

Abstract:

Raregermlinevariants(RGVar)areoneofthemajorcausesofhereditarydiseases,andalsoanimportantcomponentofcancergeneticetiology.TheaimofthisstudywastoexploretheassociationbetweengermlineRGVarandcancergeneticetiologyinChinesepopulationsbyperformingwholeexomesequencingof149candidategenesincancerfamilies.Atotalof58patientsamplesandtheirfamilymembersfromdifferenttypesofcancerfamilieswereincluded,withanagerangeof23-80yearsandamaletofemaleratiocloseto1:1.Weidentified133RGVars,including92mutationsand41DNArepeat/deletion/insertionvariants,ofwhich48wereconfirmedaspathogenicvariants.ThesevariantsmainlyinvolvedthedysregulationormutationofkeygenesrelatedtoDNArepair,cellcycleregulation,andsignaltransduction,whicharecloselyrelatedtocancergeneticetiology.FurtherfunctionalandpathwayanalysisshowedthatRGVarsplayedanimportantroleinvariouscancers,includingcolorectalcancer,gastriccancer,breastcancer,andlungcancer.Incancerfamilies,germlineRGVarwerenotlimitedtopatientsthemselves,butwidelydistributedamongothermembersofthefamily,suggestingthepossibilityoffamilialgeneticrisk.Inconclusion,thisstudyidentifiedmultiplegermlineRGVarscloselyrelatedtocancergeneticetiologybywholeexomesequencing,providingnewevidenceandreferenceforthehereditarymechanismoffamilialcancer.

Keywords:RGVar,wholeexomesequencing,cancer,geneticetiology,multigenediseaseCancerisacomplexdiseasethatcanhaveahereditarycomponent.ArecentstudyusedwholeexomesequencingtoidentifygermlineRGVars(raregeneticvariants)thatmaybecloselyrelatedtothegeneticetiologyoffamilialcancer.ThestudyfoundthatthesegermlineRGVarswerenotlimitedtocancerpatientsthemselvesbutwerewidelydistributedamongotherfamilymembers,indicatingapossibilityoffamilialgeneticrisk.

Thestudy'sfindingsprovidenewevidenceandreferenceforunderstandingthehereditarymechanismoffamilialcancer.Thisinformationcanbeusefulforearlydetection,prevention,andtreatmentofcancerinhigh-riskindividualsandfamilies.

Thestudy'suseofwholeexomesequencingallowedforacomprehensiveanalysisofgeneticvariantsassociatedwithcancerrisk.MultiplegermlineRGVarswereidentifiedthatmaycontributetothedevelopmentofcancer,andthesevariantswerefoundacrossmultiplegenes,highlightingthecomplexnatureofcancergeneticsasamultigenedisease.

Overall,thisstudy'sfindingssuggestthatgenetictestingforcancerriskmayneedtoconsidernotonlytheindividualbutalsotheirfamilymembers,astheremaybeasharedgeneticriskamongfamilymembersthatcouldincreaseanindividual'sriskfordevelopingcancerAdditionally,thestudyhighlightstheimportanceofunderstandingthepotentialimpactofenvironmentalandlifestylefactorsoncancerrisk.Whilegeneticscertainlyplayaroleincancerdevelopment,itisclearthatthereareotherfactorsatplayaswell.Forexample,exposuretocertainenvironmentaltoxinsorlifestylesbehaviorssuchassmokingorexcessivealcoholconsumptioncansignificantlyincreaseanindividual'sriskfordevelopingcertaintypesofcancer.

Interestingly,thestudyalsofoundthatcertaingeneticvariantsmaybemorestronglyassociatedwithcertaintypesofcancerthanothers.Forexample,onevariantwasfoundtobemorestronglyassociatedwithbreastcancerthananyothertype,suggestingthatindividualswiththisvariantmayhaveaparticularlyhighriskfordevelopingbreastcancer.Asmoreresearchisconductedinthisarea,itwillbeimportanttoidentifythesetypesofassociationsandtodeveloptargetedscreeningandpreventionstrategiesforindividualswhomaybeatincreasedriskforspecifictypesofcancer.

Inconclusion,thisstudyhighlightsthecomplexnatureofcancergeneticsandtheneedforamorecomprehensiveapproachtogenetictestingandcancerriskassessment.Byconsideringbothgeneticandenvironmentalfactors,aswellasthepotentialimpactofsharedgeneticsamongfamilymembers,healthcareproviderscanmoreeffectivelyidentifyindividualswhomaybeatincreasedriskforcancerandprovideappropriatescreeningandpreventivemeasures.Asresearchinthisareacontinuestoevolve,itislikelythatourunderstandingofcancergeneticsandriskassessmentwillcontinuetoexpand,ultimatelyleadingtoimprovedoutcomesforindividualswithapredispositiontothesediseasesOneofthemostpromisingareasofresearchincancergeneticsispersonalizedmedicine.Personalizedmedicineinvolvestailoringmedicaltreatmentstoanindividual'suniquegeneticmakeup,takingintoaccountvariationsintheirDNAthatmayaffectthewaytheirbodyrespondstocertaindrugsortherapies.

Throughtheuseofgenomicsequencingandanalysis,researchersarenowabletoidentifyspecificgeneticmutationsorabnormalitiesthatmaybedrivingaperson'scancer.Thisinformationcanthenbeusedtoguidethedevelopmentofpersonalizedtreatmentplansthataredesignedtotargetthespecificgeneticdriversofaperson'scancer,ratherthanrelyingonaone-size-fits-allapproach.

Oneexampleofpersonalizedmedicineinactionistheuseoftargetedtherapies,whicharedrugsthataredesignedtotargetspecificmoleculesorpathwaysinvolvedincancergrowthanddevelopment.Byidentifyingthespecificgeneticdriversofaperson'scancer,oncologistscannowmatchthemwithtargetedtherapiesthataremostlikelytobeeffective.

Anotherareaofresearchincancergeneticsisthedevelopmentofnewdiagnostictoolsandtechniquesthatcanhelptoidentifycanceratearlierandmoretreatablestages.Forexample,researchersarecurrentlyinvestigatingtheuseofliquidbiopsies,whichinvolveanalyzingaperson'sbloodforthepresenceofcirculatingtumorcellsorDNAfragments.Bydetectingcanceratitsearlieststages,healthcareproviderscanintervenewithmoreaggressivetreatmentsthathaveagreaterlikelihoodofsuccess.

Overall,thefieldofcancergeneticsholdstremendouspromiseforimprovingoutcomesforindividualsw