Germline variation at 8q24 and prostate cancer risk in men of European ancestry.
Marco MatejcicEdward J SaundersTokhir DadaevMark N BrookKan WangXin ShengAli Amin Al OlamaFredrick R SchumacherSue A InglesKoveela GovindasamiSara BenllochSonja I BerndtDemetrius AlbanesStella KoutrosKenneth Ross MuirVictoria L StevensSusan M GapsturCatherine M TangenJyotsna BatraJudith ClementsHenrik GronbergNora PashayanJohanna SchleutkerAlicja WolkCatharine WestLorelei MucciPeter KraftGeraldine Cancel-TassinKarina Dalsgaard SørensenLovise MaehleEli M GrindedalSara S StromDavid E NealFreddie C HamdyJenny L DonovanRuth C TravisRobert J HamiltonBarry RosensteinYong-Jie LuGraham G GilesAdam S KibelAna VegaJeanette T BensenManolis KogevinasKathryn L PenneyJong Y ParkJanet L StanfordCezary CybulskiBørge G NordestgaardHermann BrennerChristiane MaierJeri KimManuel R TeixeiraSusan L NeuhausenKim De RuyckAzad RazackLisa F NewcombDavor LesselRadka KanevaNawaid UsmaniFrank ClaessensPaul A TownsendManuela Gago-DominguezMonique J RoobolFlorence MenegauxKay-Tee KhawLisa A Cannon-AlbrightHardev PandhaStephen N ThibodeauDaniel J Schaidnull nullFredrik WiklundStephen J ChanockDouglas F EastonRosalind A EelesZsofia Kote-JaraiDavid V ContiChristopher A HaimanPublished in: Nature communications (2018)
Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.