The genomic landscape of familial glioma.
Dong-Joo ChoiGeorgina ArmstrongBrittney LozziPrashanth VijayaraghavanSharon E PlonTerence C WongEric BoerwinkleDonna M MuznyHsiao-Chi ChenRichard A GibbsQuinn T OstromBeatrice MelinBenjamin DeneenMelissa L Bondynull nullnull nullMatthew N BainbridgeChristopher I AmosJill S Barnholtz-SloanJonine L BernsteinElizabeth B ClausRichard S HoulstonDora Il'yasovaRobert B JenkinsChristoffer JohansenDaniel LachanceRose LaiBeatrice S MelinRyan T MerrellSara H OlsonSiegal SadetzkiJoellen SchildkrautSanjay SheteJ C AmbroseP ArumugamR BeversM BledaF Boardman-PrettyC R BoustredH BrittainM A BrownM J CaulfieldG C ChanA GiessJ N GriffinA HamblinS HendersonT J P HubbardR JacksonL J JonesD KasperaviciuteM KayikciA KousathanasL LahnsteinA LakeyS E A LeighI U S LeongF J LopezF Maleady-CroweM McEntagartF MinneciJ MitchellL MoutsianasM MuellerN MurugaesuA C NeedP O'DonovanC A OdhamsC PatchD Perez-GilM B PereiraJ PullingerT RahimA RendonT RogersK SavageK SawantR H ScottA SiddiqA SieghartS C SmithA SosinskyA StuckeyM TanguyA L Taylor TavaresE R A ThomasS R ThompsonA TucciM J WellandE WilliamsK WitkowskaS M WoodM ZarowieckiPublished in: Science advances (2023)
Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 ( P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3 , and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.