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Factors Influencing Mortality in Children with Central Nervous System Tumors: A Cohort Study on Clinical

Luz María Torres-Espíndola1, Juan Carlos Pérez-De Marcos1,2,3, Manuel Castillejos-López4

  • 1Pharmacology Laboratory, National Institute of Pediatrics, Mexico City 04530, Mexico.

Genes
|April 27, 2024
PubMed

Insights

Genetic variants in ABCB1 and ABCG2, along with the ICE chemotherapy regimen, are linked to increased mortality in pediatric patients with central nervous system tumors. Understanding these factors can inform treatment strategies for better outcomes.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacogenomics

Background:

  • Multidrug resistance (MDR) in cancer is often driven by ATP-binding cassette (ABC) transporters, reducing chemotherapy efficacy.
  • Pediatric central nervous system tumors (CNST) present unique challenges in treatment and prognosis.
  • Investigating genetic factors influencing drug transport is crucial for understanding treatment failure in CNST.

Purpose of the Study:

  • To examine the association between single nucleotide variants (SNVs) in key ABC transporter genes and mortality in pediatric CNST patients.
  • To evaluate the impact of specific genetic variations and the ICE chemotherapy regimen on patient survival.
  • To identify potential pharmacogenomic markers for improved risk stratification in pediatric CNST.

Main Methods:

  • Genotyping of 15 single nucleotide polymorphisms (SNPs) in 111 pediatric CNST patients using TaqMan probes and real-time polymerase chain reaction.
  • Clinical data collection and follow-up until death or last follow-up.
  • Survival analysis using the Cox proportional hazards model to assess the association between SNVs, chemotherapy, and mortality.

Main Results:

  • The rs1045642 variant in the ABCB1 gene was significantly associated with increased mortality risk (recessive model, HR = 2.433, p = 0.029).
  • The rs3114020 variant in the ABCG2 gene showed a significant association with mortality (codominant model, HR = 5.35, p = 0.002; dominant model, HR = 4.421, p = 0.002).
  • The ICE chemotherapy schedule was strongly associated with increased mortality across multiple models (e.g., codominant model, HR = 9.810, p ≤ 0.001).

Conclusions:

  • Specific genetic variants, namely rs1045642 in ABCB1 and rs3114020 in ABCG2, are associated with higher mortality risk in pediatric CNST patients.
  • The ICE chemotherapy regimen is a significant independent risk factor for mortality in this patient cohort.
  • These findings highlight the importance of pharmacogenomic profiling and treatment regimen selection in managing pediatric CNST.
Keywords:
ABC geneSNVcentral nervous system tumorsmortalitypediatric patients

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