title: Genetic variants in cell cycle control pathway confer susceptibility to aggressive prostate carcinoma.
abstract: BACKGROUND
  Because a significant number of patients with prostate cancer (PCa) are diagnosed with disease unlikely to cause harm, genetic markers associated with clinically aggressive PCa have potential clinical utility. Since cell cycle checkpoint dysregulation is crucial for the development and progression of cancer, we tested the hypothesis that common germ-line variants within cell cycle genes were associated with aggressive PCa.
  
  
  METHODS
  Via a two-stage design, 364 common sequence variants in 88 genes were tested. The initial stage consisted of 258 aggressive PCa patients and 442 controls, and the second stage added 384 aggressive PCa Patients and 463 controls. European-American and African-American samples were analyzed separately. In the first stage, SNPs were typed by Illumina Goldengate assay while in the second stage SNPs were typed by Pyrosequencing assays. Genotype frequencies between cases and controls were compared using logistical regression analysis with additive, dominant and recessive models.
  
  
  RESULTS
  Eleven variants within 10 genes (CCNC, CCND3, CCNG1, CCNT2, CDK6, MDM2, SKP2, WEE1, YWHAB, YWHAH) in the European-American population and nine variants in 7 genes (CCNG1, CDK2, CDK5, MDM2, RB1, SMAD3, TERF2) in the African-American population were found to be associated with aggressive PCa using at least one model. Of particular interest, CCNC (rs3380812) was associated with risk in European-American cohorts from both institutions. CDK2 (rs1045435) and CDK5 (rs2069459) were associated with risk in the African-American cohorts from both institutions. Lastly, variants within MDM2 and CCNG1 were protective for aggressive PCa in both ethnic groups.
  
  
  CONCLUSIONS
  This study confirms that polymorphisms within cell cycle genes are associated with clinically aggressive PCa. Validation of these markers in additional populations is necessary, but these markers may help identify patients at risk for potentially lethal carcinoma.
authors.affiliation: Division of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Kibel
authors.affiliation: Division of Epidemiology, Department of Environmental Medicine, NYU School of Medicine, New York, New York.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Division of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Masis
authors.initials: M
authors.lastname: Isikbay
authors.affiliation: Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Klim
authors.affiliation: Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: William S
authors.initials: WS
authors.lastname: Wu
authors.affiliation: Division of Epidemiology, Department of Environmental Medicine, NYU School of Medicine, New York, New York.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.affiliation: Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.affiliation: Departments of Genetics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: E Warwick
authors.initials: EW
authors.lastname: Daw
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D059447:Cell Cycle Checkpoints / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011467:Prostate / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins
keywords: cancer susceptibility; cell cycle; metastatic disease; prostate carcinoma; risk assessment