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Polymorphisms and methylation of the reduced folate carrier in osteosarcoma

Rui Yang1, Jing Qin, Bang H Hoang

  • 1Department of Pediatrics and Molecular Pharmacology, The Albert Einstein College of Medicine, The Children's Hospital at Montefiore, 3415 Bainbridge Avenue, Rosenthal 3rd Floor, Bronx, NY 10467, USA.

Clinical Orthopaedics and Related Research
|June 6, 2008
PubMed

Insights

Promoter methylation and 3' untranslated region polymorphisms in the reduced folate carrier gene may contribute to methotrexate resistance in osteogenic sarcoma by decreasing its expression. This impacts high-dose methotrexate treatment efficacy.

Area of Science:

  • Oncology
  • Pharmacogenetics
  • Molecular Biology

Background:

  • High-dose methotrexate is a cornerstone therapy for osteogenic sarcoma.
  • Methotrexate resistance, often due to impaired drug uptake, is a significant clinical challenge.
  • Reduced folate carrier (RFC) expression is critical for methotrexate transport into cells.

Purpose of the Study:

  • To investigate the role of RFC promoter methylation and 3' untranslated region (UTR) polymorphisms in regulating RFC expression in osteogenic sarcoma.
  • To determine if these genetic factors contribute to methotrexate resistance mechanisms.

Main Methods:

  • Analysis of 66 osteogenic sarcoma specimens.
  • Quantitative methylation-specific polymerase chain reaction (PCR) to assess promoter methylation.
  • Single-strand conformation polymorphism (SSCP) to identify 3' UTR polymorphisms.

Main Results:

  • Detectable promoter methylation was found in 84.3% of osteogenic sarcoma samples.
  • A trend indicated lower RFC mRNA levels with increased promoter methylation (>10%).
  • Heterozygous 3' UTR polymorphisms (2582 T/G, 2617C/T) were associated with significantly reduced RFC expression compared to wild-type.

Conclusions:

  • Promoter methylation and 3' UTR polymorphisms in the RFC gene are potential regulators of RFC expression in osteogenic sarcoma.
  • These epigenetic and genetic alterations may contribute to methotrexate resistance.
  • Further research is warranted to validate these findings and explore therapeutic implications.

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