Radiation-induced genomic instability

Purpose: This report reviews the data obtained in the author's laboratory over the past two decades, which support the hypothesis that radiation can induce a genome-wide process of instability in mammalian cells that is transmitted over many generations of cell replication leading to an enhanced frequency of genetic changes occurring among the progeny of the original irradiated cell. Methods: Endpoints examined are malignant transformation, delayed reproductive failure, chromosomal aberrations and mutagenesis; the relationship between these endpoints is not clear. Results: The instability phenotype was induced in approximately 10-20% of the irradiated cell population with doses of 4-12Gy, and may be induced by much smaller doses. Mutational instability can be induced by either X-rays or alpha -particles; the spectrum of DNA structural changes in mutations arising in such unstable populations differed significantly from that for direct radiationinduced mutations. Evidence is also presented for the occurrence of coincident mutations, further supporting the existence of a genome-wide process of hypermutability. Finally, data suggest that epigenetic factors acting in the host may significantly influence the development of genomic instability in vivo. Conclusions: It appears that radiation can induce a type of genomic instability in mammalian cells that is transmissible to their progeny. There remain, however, many unanswered questions concerning this phenomenon, in particular how it is initiated and how it is maintained over many generations of cell replication.