Reduced mRNA and protein expression of the genomic caretaker RAD9A in primary fibroblasts of individuals with childhood and independent second cancer.

Abstract

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 6 Issue 10 Pg. e25750 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21991345 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• RNA, Messenger
• rad9 protein

Topics

• Adolescent
• Adult
• Blotting, Western
• Cell Cycle Proteins (genetics, metabolism)
• Child
• Child, Preschool
• DNA Damage (genetics)
• DNA Repair (genetics)
• Fibroblasts (metabolism)
• Gene Expression Regulation, Neoplastic
• Genome, Human (genetics)
• Humans
• Infant
• Infant, Newborn
• Neoplasms, Second Primary (genetics)
• Protein Array Analysis
• RNA, Messenger (genetics, metabolism)
• Young Adult