Comparative analysis of HPRT mutant frequency in children with cancer

Abstract

The link between exposure to environmental mutagens and the development of cancer is well established. Yet there is a paucity of data on the relationship between gene-environment interactions and the mechanisms associated with the somatic mutational events involved with malignant transformation, especially in children. To gain insight into somatic mutational mechanisms in children who develop cancer, we determined the background mutant frequency (Mf) in the hypoxanthine phosphoribosyl transferase (HPRT) reporter gene of peripheral blood lymphocytes from pediatric cancer patients at the time of diagnosis and prior to therapeutic intervention. We studied 23 children with hematologic malignancies and 31 children with solid tumors prior to initial therapeutic intervention. Children with solid tumors, specifically sarcomas, and Hodgkin's disease were significantly older and had elevated HPRT Mfs (6.1 x 10(-6) and 3.7 x 10(-6), respectively) at the time of diagnosis, compared to normal controls (2.3 x 10(-6)) and other pediatric tumor groups including children with acute lymphocytic leukemia and non-Hodgkin's lymphoma (ALL/NHL, 1.7 x 10(-6)), central nervous system tumors (CNS, 3.6 x 10(-6)), and neuroblastoma (1.9 x 10(-6)). Of importance is that the significant differences observed in HPRT Mfs between these groups no longer existed after correcting for the effects of age. These data demonstrate that in children who develop cancer there appears to be no significant increase in background HPRT Mf that would indicate significant exposure to genotoxic chemicals or an underlying DNA repair defect resulting in genomic instability. In addition, these data demonstrate the importance of correcting for the effect of age when comparing the frequency of somatic mutations in children and should provide baseline data for future longitudinal biomonitoring studies on the genetic effects of chemotherapy in children treated for cancer.

Genotoxicity of Therapeutic Intervention in Children with Acute Lymphocytic Leukemia

“…At the time of diagnosis, the mean age of the children was 5.5 years, and, as reported in a previous paper, their CEs and lnMFs did not differ significantly from those of healthy children of the same age (23). Longitudinal analysis of Mfs at the HPRT locus was performed on 130 peripheral blood samples from 45 children.…”

Frequent HPRT mutations in paroxysmal nocturnal haemoglobinuria reflect T cell clonal expansion, not genomic instability

“…Analysis of HPRT mutations, which confer a selective advantage for cells in culture, has been utilized for this purpose (Monteiro et al , 2000; Albertini, 2001). An increase in mutant frequency (Mf) detected by HPRT has been linked to environmental exposures to mutagens such as smoking, malignancy and in cancer postchemotherapy (Abramson et al , 1999; Monteiro et al , 2000; Albertini, 2001; Rice et al , 2003). However, the assay is dependent on the proliferation of lymphocytes, mainly T cells, in the culture system.…”