1. ¹Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 6120 Executive Boulevard, EPS 7092, MSC 7238, Bethesda, MD 20892-7238, USA
2. ²Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, 7000 East Avenue, L-441, PO Box 808, Livermore, CA 94551-0808, USA

Correspondence: A Sigurdson, E-mail: sigurdsa@mail.nih.gov

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.