Genomic instability: potential contributions to tumour and normal tissue response, and second tumours, after radiotherapy

Purpose: Induced genomic instability generally refers to a type of damage w hich is transmissible down cell generations, and which results in a persist ently enhanced frequency of de novo mutations, chromosomal abnormalities or lethality in a significant fraction of the descendant cell population. The potential contribution of induced genomic instability to tumour and normal tissue response, and second tumours, after radiotherapy, is explored. Results: The phenomenon of spontaneous genomic instability is well known in some rare genetic diseases (e.g. Gorlin's syndrome),and there is evidence in such cases that it can lead to a greater propensity for carcinogenesis ( with shortened latency) which is enhanced after irradiation. It is unclear what role induced genomic instability plays in the response of normal indiv iduals, but persistent chromosomal instability has been detected in vivo in lymphocytes and keratinocytes from irradiated normal individuals. Such ind uced genomic instability might play some role in tumour response in a subse t of tumours with specific defects in damage response genes, but again its contribution to radiocurability in the majority of cancer patients is uncle ar. In normal tissues, genomic instability induced in wild-type cells leadi ng to delayed cell death might contribute to more severe or prolonged early reactions as a consequence of increased cell loss, a longer time required for recovery, and greater residual injury. In tumours, induced genomic inst ability reflected in delayed reductions in clonogenic capacity might contri bute to the radiosensitivity of primary tumours, and also to a lower incide nce, longer latency and slower growth rate of recurrences and metastases. Conclusions: The evidence which is reviewed shows that there is little info rmation at present to support these propositions, but what exists is consis tent with their expectations. Also, it is not yet clear to what extent muta tions associated with genomic instability, particularly gene polymorphisms, or other low penetrant gene mutations, contribute to the recognized spectr um of normal tissue radiosensitivity amongst cancer patients, or in the gen eral population. Tests for such genetic modifications may help in the searc h for more accurate prognostic markers of response, which hopefully could b e used in addition to other strategies to further improve the outcome for c ancer patients,given radiotherapy. (C) 2001 Elsevier Science Ireland Ltd. A ll rights reserved.