Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk
Ganna ChornokurHui‐Yi LinJonathan P. TyrerKate LawrensonJoe DennisErnest K. AmankwahXiaotao QuYa-Yu TsaiHeather JimZhihua ChenY. Ann ChenJennifer Permuth‐WeyKatja K.H. AbenHoda Anton‐CulverNatalia AntonenkovaFiona BruinsmaElisa V. BanderaYukie T. BeanMatthias W. BeckmannMaria BisognaLine BjørgeNatalia BogdanovaLouise A. BrintonAngela Brooks‐WilsonClareann H. BunkerRalf BützowIan CampbellKaren CartyJenny Chang‐ClaudeLinda S. CookDaniel W. CramerJulie M. CunninghamCezary CybulskiAgnieszka Dansonka‐MieszkowskaAndreas du BoisEvelyn DespierreEd DicksJennifer A. DohertyThilo DörkMatthias DürstDouglas F. EastonDiana EcclesRobert P. EdwardsArif B. EkiciPeter A. FaschingBrooke L. FridleyYu‐Tang GaoAleksandra Gentry‐MaharajGraham G. GilesRosalind GlasspoolMarc T. GoodmanJacek GronwaldPatricia HarringtonPhilipp HarterAlexander HeinFlorian HeitzMichelle A.T. HildebrandtPeter HillemannsClaus HøgdallEstrid HøgdallSatoyo HosonoAnna JakubowskaAllan JensenBu‐Tian JiBeth Y. KarlanLinda E. KelemenMellissa KellarLambertus A. KiemeneyCamilla KrakstadSusanne K. KjærJolanta KupryjańczykDiether LambrechtsSandrina LambrechtsNhu D. LeAlice W. LeeShashi LeleArto LeminenJenny LesterDouglas A. LevineDong LiangBoon Kiong LimJolanta LissowskaKaren H. LuJan LubińskiLene LundvallLeon F.A.G. MassugerKeitaro MatsuoValerie McGuireEsther M. JohnIain A. McNeishUsha MenonRoger L. MilneFrancesmary ModugnoKirsten B. MoysichRoberta B. NessHeli NevanlinnaUrsula EilberKunle OdunsiSara H. OlsonIrene OrlowSandra OršulićRachel Palmieri WeberJames PaulCeleste Leigh PearceTanja PejovićLiisa M. PelttariMalcolm C. PikeElizabeth M. PooleHarvey A. RischBarry P. RosenMary Anne RossingJoseph H. RothsteinAnja RudolphIngo B. RunnebaumIwona K. RzepeckaHelga B. SalvesenEva SchernhammerIra SchwaabXiao‐Ou ShuYurii B. ShvetsovNadeem SiddiquiWeiva SiehHonglin SongMelissa C. SoutheyBeata ŚpiewankiewiczLara SuchestonSoo‐Hwang TeoKathryn L. TerryPamela J. ThompsonLotte ThomsenIngvild L. TangenShelley S. TworogerAnne M. van AltenaRobert A. VierkantIgnace VergoteChristine WalshShan Wang‐GohrkeNicolas WentzensenAlice S. WhittemoreKristine G. WicklundLynne R. WilkensAnna H. WuXifeng WuYin Ling WooHannah YangWei ZhengArgyrios ZiogasHanis Nazihah HasmadAndrew BerchuckEdwin S. IversenJoellen M. SchildkrautSusan J. RamusEllen L. GoodeÁlvaro N.A. MonteiroSimon A. GaytherSteven A. NarodPaul D.P. PharoahThomas A. SellersCatherine M. Phelan
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Background Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. Results The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). Conclusion These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.Keywords:
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Abstract Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP–SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 ( P < 3.5 × 10 –9 ) and 3145 ( P < 1 × 10 –5 ) SNP–SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3 . The 3 most common gene–gene interactions were KLK3-COL4A1:COL4A2 , KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP–SNP interactions were supported by gene expression and protein–protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
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