Response to DNA damage in children as measured in the mutagen sensitivity assay. Free

1940

Several studies have found an increased risk of cancer development in adult individuals with a relatively high chromosomal instability as assessed with the mutagen sensitivity assay. The mean number of chromatid breaks per cell (b/c) in cultured lymphocytes exposed to bleomycin is used in this assay as measure of chromosomal instability. Mutagen sensitivity is inherited to a high degree and not related to exposure to environmental factors such as smoking and alcohol intake. However, a slight relation with age has been suggested. The aim of our current study is to investigate the relation between mutagen sensitivity and the development of childhood cancer. In addition, we intended to establish the influence of age on the mutagen sensitivity score. In this study we measured the b/c value in 64 children including 21 healthy volunteers (mean age 7.7 ± 6.6 y) and 43 children (retinoblastoma (Rb n=19), acute lymphoblastic leukemia (ALL n=10), acute myeloid leukemia (AML n=4), brain tumor (n=10)) with a cancer history (mean age 8.3 ± 6.7 y). We also included 4 healthy volunteers and 3 cancer patients (including one transient myelodysplastic syndrome) with Down syndrome. Results: A positive correlation between age and b/c value was found in both the cancer patients and the control group (R=0.52 and R=0.59; p<0.005 respectively). Moreover, the mean b/c value in healthy Down syndrome children (b/c= 0.78) was significantly higher compared to control children (mean b/c= 0.50; p=0.026) and the three Down syndrome patients with cancer were even more sensitive (mean b/c=0.94). This confirms the chromosomal instability in Down syndrome children and implies that the relation with cancer development should be explored. Overall, no difference was found in mutagen sensitivity between healthy volunteers and cancer patients (mean b/c= 0.50 vs. mean b/c=0.47, respectively). Nevertheless, stratification on tumor type showed that children with AML and with a type of brain tumor (ependymoma n=2) had an increased mean b/c value of 0.76 and 0.64, respectively. Interestingly, in contrast, the children with hereditary retinoblastoma had a relatively low mean b/c level (0.31, n=9), which implies that another mechanism plays a role in this patient group, which should be assessed with different assays. In general, these results suggest that there might be a role for chromosomal instability in the etiology of AML and brain tumors. Groups will be extended and more tumor types will be investigated in the future. The significant increase in b/c levels with age is much stronger as compared to what has been reported for adults and this requires correction for age in statistical analysis of mutagen sensitivity studies. It will also be worthwhile to investigate the relation between high mutagen sensitivity in children with cancer and increased adverse side effects, response to therapy and development of secondary cancer later in life.