Second cancers after radiotherapy: any evidence for radiation-induced genomic instability?

Abstract

Do second primary cancers in humans arise from radiation-induced somatic genomic instability after radiotherapy for the first malignancy? The amount of truly pertinent human information on this issue is sparse, leading to the conclusion that we cannot confirm or refute that instability induction by radiation is involved. However, the in vitro findings of radiation-induced genomic instability through bystander effects or increased mutation rates in cell progeny of apparently normal but irradiated cells are provocative and their transferability to human in vivo biology deserves further investigation. We describe possible animal and human studies to stimulate ideas, but the collaborative commitment of multiple large institutions to tumor tissue procurement and retrieval will be essential. In addition, detecting the temporal progression of genomic instability and identifying the salient genetic events as being radiation-induced will be pivotal. Execution of some of the studies suggested is not possible now, but applying next-generation methods could bring the concepts to fruition. As nearly one in 10 cancer diagnoses are second (or higher) malignancies, it is important to understand the contribution of radiotherapy to second cancer induction and pursue well-coordinated efforts to determine the role of induced genomic instability.

Genomic instability in radiation-induced mouse lymphoma from p53 heterozygous mice

“…Ionizing radiation is a known carcinogen that has been implicated in the etiology of a number of human tumors, including breast cancer, glioma, lymphoma and sarcoma , but the role of induced genetic instability in the process of human carcinogenesis remains controversial (Marx, 2002;Sigurdson and Jones, 2003). Radiation causes damage to DNA directly by the induction of double strand breaks (DSBs), or indirectly by generation of reactive oxygen species that damage sugar and base residues.…”

Bystander signaling between glioma cells and fibroblasts targeted with counted particles

“…10,23,24 It has been suggested that the radiation-induced bystander effects, including genomic instability and increased mutation, may contribute to second cancer induction in normal cells after radiotherapy. 25 Most of the previous studies of bystander effects focused on the radiation-induced responses within a cell population or cluster consisting of the same cell type. Recently, however, bystander responses have been reported in a 3-dimensional ureter primary tissue model after microbeam irradiation.…”

Chromosome analysis in childhood cancer survivors and their offspring—No evidence for radiotherapy-induced persistent genomic instability

“…The recognition that second cancers in patients who have received radiotherapy are related to the treatment for their first malignancy provided the focus for a recent review which examined whether such cancers could have arisen from radiation-induced genomic instability [39]. However, it was concluded that current studies do not provide sufficient evidence to determine if the phenomenon contributes to secondary malignancies after radiotherapy.…”