Abstract

Cutaneoussquamouscellcarcinoma(cSCC)isthesecondmostcommoncancerintheUnitedStates, affectingoveramillionpeopleannually,andwithsignificantmortalityduetometastasis.Despiteitprevalence andhightreatmentcosts,cSCCsarenotincludedinlarge-scalecancergenomicseffortsaimedat understandingthegeneticchangesarisingincancercells,suchasTheCancerGenomeAtlas(TCGA)project. Thus,genomicalterationsincSCChavenotbeencomprehensivelycharacterized,andnovel,molecularly- targetedtreatmentshavenotbeendeveloped.Thisproposal,modeledafterTCGAwhichisco-ledbyDr.Gad Getz(Co-Iofthisapplication),representsthelargesteffortofitskindtoanalyzegenomicchangesthatdrive cSCCprogression.Thiscriticaldataisneededtoidentifytargetsfornoveltreatmentandpreventionstrategies ofcSCC.Ourteamwasthefirsttopublishagenome-wideassociationstudythatidentifiedtennovelgermline lociassociatedwithincreasedcSCCriskusingthelargeGeneticEpidemiologyResearchonAging(GERA) cohort.Theoverallscientificobjectiveofthisproposalistoidentifyandintegratenoveltumor mutationaldatawithpreviouslycharacterizedinformationonhostgeneticriskfactorsandclinicalrisk factorstobetterunderstandhowcancerriskallelescontributetothedevelopmentofcSCCscapableof metastasis.Wewillanalyze290cSCCs(145primarycSCCsthatprogressedtometastasisand145non- metastaticprimarycSCCs)arisinginthewell-characterizedGERAcohorttoprovideacomprehensive landscapeofgenomicalterationsincSCCs.Weproposethefollowingspecificaims:1)characterizethe genomeandtransciptomeof290cSCCswithexistinggermlinedatausingatieredapproachincludingwhole- exome,whole-genome,andRNAsequencingtoidentifydrivermutations,aswellasepigenomicchanges;?2) integratethesomaticmutationalanalysiswithenvironmentalexposuredatatounderstandhowenvironmental exposuresimpactcSCCswithdistinctsomaticmutationalprofiles;?and3)developaclinicallymeaningfulrisk predictiontoolforidentifyingsubjectsatriskformetastaticcSCCsthatcombinesgermline,somatic,and clinicaldata.Theapproachisinnovativebecauseitwillincreaseunderstandingofthejointcontributionofthe germlineandsomaticgenomesforcSCCriskanditwillcreateapubliclyaccessiblecSCCgenomicdataportal providinganovelresourceforthescientificcommunity.Theproposedresearchissignificantbecauseitwill integrategermlineandsomaticgeneticdatatogainacomprehensivepictureofhowthegeneticsofboththe personandthetumorinteracttoaffectcSCCevolutionandprogression.Thecomprehensive,integrated characterizationofkeygenomicchangesinoneofthemostprevalentandcostlycancerswillsupport advancesindevelopingmoreeffectivewaystodiagnose,treatandpreventcSCCsandpotentiallysquamous cellcarcinomaarisinginotherorgans.

Public Health Relevance

PUBLICHEATHRELEVANCE Cutaneoussquamouscellcarcinoma(cSCC)isthesecondmostcommoncancerinAmericaandwhen itmetastasizes,ithashighdisease-associatedmortality.ToimproveunderstandingofcSCCetiologyand biology,itiscriticaltounderstandtheconnectionbetweengermline(person)andacquiredsomatic(tumor) genomes,particularlythosealterationsassociatedwithaggressivetumorsthatmetastasize.Weproposeto identifytumormutationaldataandtointegratethisdatawithourpreviouslyidentifiedgermlinedatato understandthegeneticinteractionsofthepersonandtumorincSCCevolution.Thecomprehensive,integrated characterizationofkeygenomicchangesinoneofthemostprevalentandcostlycancerswillsupport advancesindevelopingmoreeffectivewaystodiagnose,treatandpreventcSCCs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA231264-02
Application #
9916722
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Carrick, Danielle M
Project Start
2019-04-16
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114