Genetic variants in cell cycle control pathway confer susceptibility to aggressive prostate carcinoma

Adam S. Kibel, Jiyoung Ahn, Masis Isikbay, Aleksandra Klim, William S. Wu, Richard B. Hayes, William B. Isaacs, E. Warwick Daw

Research output: Contribution to journalArticlepeer-review

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. Prostate 76:479-490, 2016.

Original languageEnglish (US)
Pages (from-to)479-490
Number of pages12
JournalProstate
Volume76
Issue number5
DOIs
StatePublished - Apr 1 2016

Keywords

  • cancer susceptibility
  • cell cycle
  • metastatic disease
  • prostate carcinoma
  • risk assessment

ASJC Scopus subject areas

  • Oncology
  • Urology

Fingerprint

Dive into the research topics of 'Genetic variants in cell cycle control pathway confer susceptibility to aggressive prostate carcinoma'. Together they form a unique fingerprint.

Cite this