Reduced mRNA and Protein Expression of the Genomic Caretaker RAD9A in Primary Fibroblasts of Individuals with Childhood and Independent Second Cancer

نویسندگان

  • Eva Weis
  • Holger Schoen
  • Anja Victor
  • Claudia Spix
  • Marco Ludwig
  • Brigitte Schneider-Raetzke
  • Nicolai Kohlschmidt
  • Oliver Bartsch
  • Aslihan Gerhold-Ay
  • Nils Boehm
  • Franz Grus
  • Thomas Haaf
  • Danuta Galetzka
چکیده

BACKGROUND The etiology of secondary cancer in childhood cancer survivors is largely unclear. Exposure of normal somatic cells to radiation and/or chemotherapy can damage DNA and if not all DNA lesions are properly fixed, the mis-repair may lead to pathological consequences. It is plausible to assume that genetic differences, i.e. in the pathways responsible for cell cycle control and DNA repair, play a critical role in the development of secondary cancer. METHODOLOGY/FINDINGS To identify factors that may influence the susceptibility for second cancer formation, we recruited 20 individuals who survived a childhood malignancy and then developed a second cancer as well as 20 carefully matched control individuals with childhood malignancy but without a second cancer. By antibody microarrays, we screened primary fibroblasts of matched patients for differences in the amount of representative DNA repair-associated proteins. We found constitutively decreased levels of RAD9A and several other DNA repair proteins in two-cancer patients, compared to one-cancer patients. The RAD9A protein level increased in response to DNA damage, however to a lesser extent in the two-cancer patients. Quantification of mRNA expression by real-time RT PCR revealed lower RAD9A mRNA levels in both untreated and 1 Gy γ-irradiated cells of two-cancer patients. CONCLUSIONS/SIGNIFICANCE Collectively, our results support the idea that modulation of RAD9A and other cell cycle arrest and DNA repair proteins contribute to the risk of developing a second malignancy in childhood cancer patients.

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عنوان ژورنال:

دوره 6  شماره 

صفحات  -

تاریخ انتشار 2011