Abstract
The purpose of the present study was to investigate whether former childhood cancer patients who developed a subsequent secondary primary neoplasm (SPN) are characterized by elevated spontaneous chromosomal instability or cellular and chromosomal radiation sensitivity as surrogate markers of compromised DNA repair compared to childhood cancer patients with a first primary neoplasm (FPN) only or tumor-free controls. Primary skin fibroblasts were obtained in a nested case-control study including 23 patients with a pediatric FPN, 22 matched patients with a pediatric FPN and an SPN, and 22 matched tumor-free donors. Clonogenic cell survival and cytogenetic aberrations in Giemsa-stained first metaphases were assessed after X-irradiation in G1 or on prematurely condensed chromosomes of cells irradiated and analyzed in G2. Fluorescence in situ hybridization was applied to investigate spontaneous transmissible aberrations in selected donors. No significant difference in clonogenic survival or the average yield of spontaneous or radiation-induced aberrations was found between the study populations. However, two donors with an SPN showed striking spontaneous chromosomal instability occurring as high rates of numerical and structural aberrations or non-clonal and clonal translocations. No correlation was found between radiation sensitivity and a susceptibility to a pediatric FPN or a treatment-associated SPN. Together, the results of this unique case-control study show genomic stability and normal radiation sensitivity in normal somatic cells of donors with an early and high intrinsic or therapy-associated tumor risk. These findings provide valuable information for future studies on the etiology of sporadic childhood cancer and therapy-related SPN as well as for the establishment of predictive biomarkers based on altered DNA repair processes.
Highlights
Over the past decades, the number of cancer survivors increased constantly due to earlier diagnosis as well as optimized and new oncologic therapies with increased effectiveness in local and systemic tumor control [1]
We examined spontaneous chromosome aberrations as well as cellular and chromosomal ionizing radiation (IR) sensitivity in primary skin fibroblasts obtained from a carefully matched case-control study nested in a cohort of childhood cancer survivors who were successfully treated for a sporadic first primary neoplasm (FPN) and either developed an second primary neoplasms (SPN) or not
Since no matching of oncologic therapies has been performed between the corresponding FPN and SPN cases, differences in the application of radiation therapy (RT) were noted as follows: Four SPN and two FPN cases received radiochemotherapy compared to their respective FPN and SPN counterparts treated with CT only
Summary
The number of cancer survivors increased constantly due to earlier diagnosis as well as optimized and new oncologic therapies with increased effectiveness in local and systemic tumor control [1]. The benefit of prolonged survival of cancer patients is compromised by an elevated risk for therapy-related adverse late-effects, with second primary neoplasms (SPN) representing the heaviest burden for the patients [2]. This is of particular concern for the treatment of highly cancer-prone individuals with pediatric malignancies who are at the utmost risk for SPN because of high innate susceptibility, the clastogenic impact of anti-tumor treatments and prolonged survival after effectual cancer therapy with an average 5-year survival rate of about 80% [3]. Despite such correlations there is still a large variation in the individual susceptibility to treatment-induced SPN which has been attributed to genetic variation
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