Long telomeres cooperate with p53, MDM2, and p21 polymorphisms to raise pediatric solid tumor risk

Pediatr Int. 2019 Aug;61(8):759-767. doi: 10.1111/ped.13915.

Abstract

Background: While leukocyte telomere length has been linked with altered risk in adult cancer, limited information is available on its association with risk in pediatric solid tumors. We investigated the association of telomeric alterations with risk of pediatric solid tumors. We also investigated whether altered telomeres cooperated with the TP53 rs1042522, MDM2 rs2279744 and CDKN1A (p21cip1 ) rs1059234 single-nucleotide polymorphisms to modify cancer risk.

Methods: A total of 101 tumor patients and 202 controls were recruited for this age- and gender-matched case-control study. Relative telomere length (RTL) was determined in peripheral blood leukocytes using quantitative real-time polymerase chain reaction (PCR), and the polymorphisms were genotyped using PCR-restriction fragment length polymorphism.

Results: Using median RTL in the healthy controls as a cut-off, children with longer telomeres were at an increased risk of developing a solid tumor (OR, 2.70; P < 0.01). When participants were categorized according to control RTL quartiles, a significant dose-response relationship was observed (χ2 = 10.95; P < 0.001). The risk for tumors increased nearly threefold (P = 0.001) for the triple interaction RTL × TP53 rs1042522 × p21cip1 rs1059234 compared with the maximum effect of any single factor, although the interaction effect was less than additive. The MDM2 rs2279744 GG genotype reduced pediatric solid tumor risk significantly (OR, 0.51).

Conclusion: Combined analysis of telomeres and genetic polymorphisms in the TP53 pathway can provide important clues to understanding pediatric solid tumor etiology.

Keywords: MDM2; TP53; p21 cip1; pediatrics; telomere; tumor.

MeSH terms

  • Adolescent
  • Amplified Fragment Length Polymorphism Analysis
  • Biomarkers, Tumor / genetics*
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Female
  • Genes, p53 / genetics*
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Neoplasms / diagnosis
  • Neoplasms / genetics*
  • Polymorphism, Single Nucleotide*
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • Real-Time Polymerase Chain Reaction
  • Risk Assessment
  • Sensitivity and Specificity
  • Telomere Homeostasis*

Substances

  • Biomarkers, Tumor
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2