Abstract
BackgroundThe 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/FindingsTo 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/SignificanceCollectively, 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.
Highlights
In most cases, cancer is a multifactorial disease caused by environmental hazards, unhealthy lifestyle and/or genetic factors [1]
Compared to the enormous efforts to characterize the transcriptomes and proteomes of tumor cells, there are relatively few studies searching for gene expression differences in normal somatic cells of tumor patients [13,14]
To test the hypothesis that differences in DNA repair pathways may influence the risk for developing a second tumor following treatment of childhood cancer, we compared the constitutive levels of DNA repairassociated proteins in primary fibroblasts of matched two-cancer and one-cancer patients
Summary
Cancer is a multifactorial disease caused by environmental hazards, unhealthy lifestyle and/or genetic factors [1]. Only a small proportion (1–10%) of childhood cancers has a known genetic etiology [3]. Radiation and/or chemotherapy constitute risk factors for development of a second malignancy, which cannot be classified as remission of the primary tumor. Because relatively few childhood cancer survivors develop a second malignancy [6], genetic predisposition may be involved. 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
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