6533b7d9fe1ef96bd126c3e4
RESEARCH PRODUCT
A Genome-wide Association Study of Early-onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age
Douglas F. EastonRachelle BrutusEsther M. JohnEsther M. JohnIrene L. AndrulisQuinten WaisfiszMelissa C. SoutheyDaniel F. SchmidtNancy J. CoxValerie McguireFernando RivadeneiraPaul D.p. PharoahBrandon L. PierceMark LathropMark A. JenkinsCarmel ApicellaC. BlomqvistSteve GallingerDaniela SeminaraPolly A. NewcombGraham G. GilesGraham G. GilesAlfons MeindlAlison M. DunningKathi MaloneHeli NevanlinnaDieter Flesch-janysHabibul AhsanDavid V. ContiShantanu RoyStephanie MelkonianHanne Meijers-heijboerRebecca HeinRebecca HeinLin TongMaria ArgosDavid DugganKyriaki MichailidouNazneen RahmanStephen J. ChanockClare TurnbullEric R. GamazonBertram Müller-myhsokJenny Chang-claudeIsabel Dos Santos SilvaNoralane M. LindorAnna FelbergOlivia FletcherDan L. NicolaePer HallKamila CzeneDavid J. HunterKristiina AittomäkiJulia A. KnightJohn L. HopperAstrid IrwantoJennifer StoneEnes MakalicNorbert DahmenJianxin ShiMagdalena LochmannFarzana JasmineEunjung LeeRobert W. HaileRegina M. SantellaJianjun LiuLars BeckmannDaniel J. ParkMarilie D. GammonJerry HalpernAndré G. UitterlindenGraham CaseyAlice S. WhittemoreQuang M. BuiDuncan C. ThomasRita K. SchmutzlerJulian PetoGiske UrsinMuhammad G. Kibriyasubject
EpidemiologyPopulationGenome-wide association studySingle-nucleotide polymorphismBreast NeoplasmsBiologyPolymorphism Single NucleotideArticle03 medical and health sciences0302 clinical medicineBreast cancerSDG 3 - Good Health and Well-beingPhosphofructokinase-1 Muscle TypeGenetic predispositionmedicineBiomarkers TumorSNPHumansGenetic Predisposition to DiseaseeducationGene030304 developmental biologyGenetics0303 health scienceseducation.field_of_studyMiddle Agedmedicine.disease3. Good healthOncologyPFKM030220 oncology & carcinogenesisCase-Control StudiesFemaleGenome-Wide Association Studydescription
Abstract Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10−6. In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-01-01 |