Protein-altering germline mutations implicate novel genes related to lung cancer development.
Xuemei JiSemanti MukherjeeMaria Teresa LandiYohan BossePhilippe JoubertDakai ZhuIvan GorlovXiangjun XiaoYounghun HanOlga GorlovaRayjean J HungYonathan BrhaneRobert Carreras-TorresDavid Chistopher ChristianiNeil CaporasoMattias JohanssonGeoffrey LiuStig Egil BojesenLoic Le MarchandDemetrios AlbanesHeike BickeböllerMelinda C AldrichWilliam S BushAdonina TardónGadi RennertChu ChenJinyoung ByunKonstantin H DragnevJohn K FieldLambertus Fa KiemeneyPhilip LazarusShan ZienolddinyStephen LamMatthew B SchabathAngeline S AndrewPier A BertazziAngela Cecilia PesatoriNancy DiaoLi SuLei SongRuyang ZhangNatasha LeighlJakob Sidenius JohansenAnders MellemgaardWalid SalibaChristopher HaimanLynne WilkensAna Fernandez-SomoanoGuillermo Fernandez-TardónErik H F M van der HeijdenJin Hee KimMichael P A DaviesMichael W MarcusHans BrunnströmJonas ManjerOlle MelanderDavid C MullerKim OvervadAntonia TrichopoulouRosario TuminoGary E GoodmanAngela CoxFiona TaylorPenella WollErich WichmannThomas MuleyAngela RischAlbert RosenbergerKjell GrankvistMikael JohanssonFrances ShepherdMing Sound TsaoSusanne M ArnoldEric B HauraCiprian Nicolae BolcaIvana HolcatovaVladimir JanoutMilica KonticJolanta LissowskaAnush MukeriyaSimona OgnjanovicTadeusz M OrlowskiGhislaine SceloBeata SwiatkowskaDavid ZaridzePer BakkeVidar SkaugLesley M ButlerKenneth OffitPreethi SrinivasanChaitanya BandlamudiMatthew D HellmannDavid B SolitMark E RobsonCharles M RudinZsofia K StadlerBarry S TaylorMichael F BergerRichard S HoulstonJohn McLaughlinVictoria L StevensDavid C NickleMa'en ObeidatHidde J HaismaMaría Soler ArtigasSanjay SheteHermann BrennerStephen J ChanockPaul J BrennanJames D McKayChristopher Ian AmosPublished in: Nature communications (2020)
Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.