Genetic susceptibility to cancer: ICRP Publication 79

Abstract

A Task Group of the ICRP Committee 1 (Radiation Effects) has reviewed relevant data with the objective of advising the Main Commission of the ICRP on the possible implications for radiological protection of emerging views on genetic susceptibility to cancer (Chapter 1). Chapter 2 considers DNA damage and its processing/repair after ionising radiation and serves principally to demonstrate that a few rare cancer-prone, human recessive genetic disorders show DNA repair deficiency and profound increases in radiosensitivity. Less dramatic changes in radiosensitivity are also apparent in a wider range of such disorders. The cellular mechanisms that underly the association between DNA damage processing and tumorigenesis are discussed. Chapter 3 reviews the mechanisms and genetics of solid tumours illustrating the ways in which mutations in proto-oncogenes, tumour suppressor genes together with those in DNA repair and cell cycle control genes can contribute to tumour development. Specific examples are given of how germ line mutation of such genes can predispose to familial cancer. It is judged that up to 5% of all solid tumours have a recognisable genetic component. Heritable organ-specific effects are most usual and cancers of the breast and colon tend to show the most obvious genetic components. Clearly discernible genetic effects are seen when rare dominant germ line mutations express strongly as familial cancer (high penetrance mutations), but the existence of perhaps less rare low penetrance mutations and gene–gene interactions are recognised but not well understood. Chapter 4 considers the mechanisms and genetics of lympho-haemopoietic tumours. Specific chromosomal translocations and proto-oncogene activation events are much more frequent in human leukaemia/lymphoma than in solid tumours. Genetic predisposition to leukaemia/lymphoma is found in a number of non-familial recessive genetic disorders of DNA processing and/or chromosomal instability. Familial manifestation of susceptibility to these tumours is, however, extremely rare. The genetic component, although poorly defined, is judged to be less than that of solid tumours and expressed largely in childhood. Chapter 5 reviews and discusses limited data that comment upon tumorigenic radiosensitivity in cancer-prone genetic conditions. From knowledge of the fundamental processes involved it is judged that in most, but not all, cases genetic susceptibility to spontaneous tumours will be accompanied by a greater-than-normal risk after radiation. A review of epidemiological, clinical and experimental data relevant to this issue suggests that although a wide range of different sensitivities may be involved, a factor of 10 increase in sensitivity broadly accords with the limited human data available. This interim judgement of a factor of 10 increase in radiation risk in such human genetic disorders is made for the purposes of illustrative modelling and calculation. In addition, specific attention is given to breast cancer risk in heterozygotes for the radiosensitive human disorder, ataxia-telangiectasia; this association, while in no way discounted, is judged to be less strong than that claimed by some. Chapter 6 discusses and develops computational modelling procedures that aim to describe the impact of genetic factors on radiation-tumorigenesis in human populations. Estimates of the prevalence of known cancer-prone genetic disorders are made but breast cancer susceptibility is used to illustrate the application of the model developed. The most important message to emerge from this work is that, even at an assumed high level of radiation sensitivity, the prevalence of familial (high penetrance) genetic disorders in the population is too low (<1%) for there to be a significant impact on risk in typical human populations. In principle, however, there is the potential for such impact in atypical inbred sub-populations where these mutations can be more common. These modelling procedures are also used to illustrate how incomplete penetrance of these mutations will dilute any impact on population risk. In conjunction with the Main Commission of the ICRP, in Chapter 7 the Task Group discusses the potential implications of the main report for radiological protection. Their principal conclusions are: (i) That current estimates of radiation cancer risk already include an unknown contribution from genetically radiosensitive sub-populations. (ii) Using the data cited, the likely contribution to radiation risk from familial cancer disorders is too low to generate an unacceptable distortion of current estimates of cancer risk in the vast majority of human populations. (iii) There is insufficient knowledge to judge the contribution to risk from mutations of low penetrance that do not express as familial cancer. (iv) Because of the high risk of spontaneous cancer in familial disorders, low doses of radiation (say 100 mSv) are most unlikely to impact significantly on life-time cancer risk in an affected individual; at high doses, such as those experienced in radiotherapy, this relative risk may however become important. (v) Because organ-specific cancer risk is predicted in most familial disorders, the absolute increase overall in risk to an affected individual will be diluted, ie. comparing normal and affected individuals. (vi) The utility of genetic testing for cancer predisposition in the context of radiological protection is currently limited by technical factors and concerns on predictive power. In the future genetic testing may find selected use prior to certain medical exposures to radiation, but the value of such procedures, as applied to low-dose occupationally exposed individuals, is open to doubt; it would also be subject to major ethical scrutiny outside the remit of the ICRP. The Task Group and the Main Commission of the ICRP stress that, because of the current lack of knowledge, the above judgements should be regarded as preliminary. The report serves principally to provide a framework on which to develop further views in this rapidly advancing area of human genetics.