Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.
Maria Teresa LandiD Timothy Timothy BishopStuart MacgregorMitchell J MachielaAlexander J StratigosPaola GhiorzoMyriam BrossardDonato CalistaJiyeon ChoiMaria Concetta FargnoliTongwu ZhangMonica RodolfoAdam J TrowerChiara MeninJacobo MartinezAndreas HadjisavvasLei SongIrene StefanakiRichard A ScolyerRose YangAlisa M GoldsteinMiriam PotronyKaterina P KypreouLorenza PastorinoPaola QueiroloCristina PellegriniLaura CattaneoMatthew ZawistowskiPol Gimenez-XavierArantxa RodriguezLisa ElefantiSiranoush ManoukianLicia RivoltiniBlair Hamilton SmithMaria A LoizidouLaura Del RegnoDaniela MassiMario MandalaKiarash KhosrotehraniLars A AkslenChristopher Ian AmosPer A AndresenMarie-Françoise AvrilEsther AziziHans Peter SoyerVeronique BatailleBruna DalmassoLisa M BowdlerKathryn P BurdonWei V ChenVeryan CoddJamie E CraigTadeusz DębniakMario FalchiShenying FangEitan FriedmanSarah SimiPilar GalanZaida Garcia-CasadoElizabeth M GillandersScott D GordonAdele GreenNelleke A GruisJohan HanssonMark HarlandJessica HarrisPer HelsingAnjali HendersMarko HočevarVeronica HöiomDavid HunterChristian IngvarRajiv KumarJulie LangG Mark LathropJeffrey E LeeXin LiJan LubińskiRona M MackieMaryrose MaltJosep MalvehyKerrie McAloneyHamida MohamdiAnders MolvenEric K MosesRachel E NealeSrdjan NovakovićDale R NyholtHåkan OlssonNicholas OrrLars G FritscheJoan Anton Puig-ButilleAbrar A QureshiGraham L Radford-SmithJuliette Randerson-MoorCelia RequenaCasey RoweNilesh J SamaniMarianna SannaDirk SchadendorfHans-Joachim SchulzeLisa A SimmsBernard Mark SmithersFengju SongAnthony J SwerdlowNienke van der StoepNicole A KukutschAlessia ViscontiLeanne WallaceSarah V WardLawrie WheelerRichard A SturmAmy HutchinsonKristine JonesMichael MalaskyAurelie VogtWeiyin ZhouKaren A PooleyDavid E ElderJiali HanBelynda D HicksNicholas K HaywardPeter A KanetskyChad BrummettGrant W MontgomeryCatherine M OlsenCaroline HaywardAlison M DunningNicholas G MartinEvangelos EvangelouGraham J MannGeorgina LongPaul David Peter PharoahDouglas F EastonJennifer H BarrettAnne E CustGoncalo AbecasisDavid L DuffyDavid C WhitemanHelen GogasArcangela De NicoloMargaret A TuckerJulia A Newton-Bishopnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullKetty PerisStephen J ChanockFlorence DemenaisKevin M BrownSusana PuigEduardo NagoreJianxin ShiMark M IlesMatthew H LawPublished in: Nature genetics (2020)
Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10-8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.