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Genetic alterations of Cyclin D-CDK4/6-INK4-RB pathway in prostate cancer

Monika Kmeťová Sivoňová1, Márk Híveš1, Ján Kliment2

  • 1Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic.

Molecular Biology Reports
|April 30, 2025
PubMed
Abstract

Insights

Genetic variations in cell cycle regulators like cyclin D1 are linked to prostate cancer risk. Altered expression of CCND1, p15INK4b, and RB genes was observed in tumor tissues, suggesting their role in prostate cancer development.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Cell cycle dysregulation is a hallmark of cancer.
  • Key regulators of the cell cycle include cyclin-dependent kinases (CDKs), cyclins, CDK inhibitors, and the retinoblastoma protein (RB).
  • Polymorphisms and altered gene expression in these regulators may influence cancer susceptibility and progression.

Purpose of the Study:

  • To investigate the association between polymorphisms in CDK4, CDK6, CCND1, p16INK4a, p15INK4b, and RB genes and prostate cancer risk.
  • To examine the mRNA expression levels of these genes in prostate tumor tissues compared to benign prostatic hyperplasia (BPH) tissues.
  • To correlate gene expression with clinical parameters such as PSA levels and pathological T stage.

Main Methods:

  • Genotyping of specific single nucleotide polymorphisms (SNPs) in CDK4, CDK6, CCND1, p16INK4a, p15INK4b, and RB using TaqMan® SNP Assays.
  • Quantitative real-time PCR (qRT-PCR) to measure mRNA expression levels of the studied genes in tumor and BPH tissues.
  • Statistical analysis to assess associations between polymorphisms, gene expression, and prostate cancer risk, PSA levels, and T stage.

Main Results:

  • The CCND1 rs9344 polymorphism (GA genotype) was significantly associated with an increased risk of prostate cancer.
  • Relative mRNA expression of CCND1, p15INK4b, and RB was significantly lower in prostate tumor tissues than in BPH tissues.
  • Lower CDK4 and p16INK4a mRNA expression correlated with elevated PSA levels, and reduced p15INK4b expression was linked to higher pathological T stage.

Conclusions:

  • Genetic variations, including polymorphisms and altered gene expression within the cyclin D1-CDK4-p16INK4a/p15INK4b-RB pathway, are associated with prostate cancer risk.
  • The CCND1 gene and its pathway members show potential as biomarkers for prostate cancer risk and progression.
Keywords:
Cell cycleExpressionPolymorphismProstate cancerSlovak population

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