Mutagenesis, Vol. 14, No. 5, 521-525,
September 1999
© 1999 UK Environmental Mutagen Society/Oxford University Press
Meeting report
Department of Health, Skipton House, Elephant and Castle, London SE1 6LH, UK
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Joint COC/COM symposium on genetic susceptibility to cancer, Department of Health, London, UK, October 1998 |
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 Top Joint COC/COM symposium on... Overview, susceptibility to...Metabolic polymorphisms,...References |
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A joint symposium of the UK Department of Health* Advisory Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment (COC) and the Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM) was held on 19 October 1998 at Skipton House, Elephant and Castle, London, UK. The meeting was attended by members of COC and COM and the Committee on Medical Aspects of Radiation in the Environment (COMARE), representatives from the National Radiological Protection Board (NRPB), the Chairman of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT), invited speakers and delegates from various Government Departments.
COC and COM are independent expert advisory committees appointed by the Chief Medical Officer (CMO). The Committees advise the CMO and, through the CMO, the Government, on all aspects related to the carcinogenicity and mutagenicity of chemicals. Both Committees also have a general remit to advise on important general principles or new scientific discoveries in connection with carcinogenic/mutagenic risks, to coordinate with other bodies concerned with the assessment of carcinogenic/mutagenic risks and to present recommendations for testing. The purpose of the symposium was to bring together experts in the fields of molecular toxicology, genetic epidemiology, carcinogenicity and mutagenicity in order to increase understanding of genetic susceptibility to cancer. The morning session focused on different factors that influence the induction of mutations in somatic and germ cells and the mechanisms for some of these which have been explained by molecular studies. The afternoon session considered presentations on metabolic polymorphisms responsible for individual differences in the biotransformation of mutagens and carcinogens and also on studies used to investigate these in populations.
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Overview, susceptibility to mutagens and some mechanisms |
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TopJoint COC/COM symposium on...Overview, susceptibility to...Metabolic polymorphisms,...References |
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Professor J. Parry (University of Wales Swansea), Chairman of COM, gave a brief introduction to the session and welcomed delegates on behalf of himself and Professor P. Blain (University of Newcastle), Chairman of COC. Professor Parry commented that committees like COM and COC might have to consider data which pertained to individual risk assessment rather than, as at present, population risks. The purpose of the symposium was to address the subject of genetic susceptibility to mutagens and carcinogens. The consequences of individual susceptibility were not always predictable and he highlighted this using the example of unexpected variation in chemical sensitivity of cells from xeroderma pigmentosum (XP) patients. Although these individuals are nucleotide excision repair deficient, there was no direct correlation between the extent of this lack of repair and tumour formation (apart from the sensitivity to skin tumours induced by UV). When primary cultures of XP cells were investigated there was no difference in their chromosome stability, but if these cells were exposed to low levels of a chemical such as colcimid (which disrupts the cell cycle), a sensitivity was found which had not been previously predicted. Thus, this was an example of how a genetic defect in DNA repair influenced the sensitivity of cells to a spindle inhibitor in a somewhat unpredictable way. Professor Parry concluded that an understanding of the variation in DNA repair activity between specific tissues and also between individuals was essential in attempting to estimate the consequences of exposure to genotoxic and carcinogenic chemicals.
Dr J. Favor (Institute of Mammalian Genetics, Neuherberg, Germany) presented an overview of mammalian germ cell mutagenesis, in particular the mouse specific locus test (SLT), including how and why it was used. He noted that the process of gametogenesis in mammals was associated with cell differentiation at the genetic, morphological and metabolic levels and also that germ cell stages exhibited differences in DNA synthesis, chromosome associated proteins and the ability to repair DNA damage. Sensitivity to mutation induction could be influenced by such factors due to the accessibility of DNA to insult by chemical mutagens and the interval between DNA damage and the next round of replication, as well as the repair of DNA damage. He presented data for ethylnitrosourea (ENU), a model mutagen, using the SLT to indicate the complexities of mutation induction in vivo.
The SLT was developed as an assay to measure quantitatively the transmission to offspring of gene mutations induced in mammalian germ cells. The test detected genetic changes that resulted in full or partial loss of function in any of seven defined marker genes that control certain externally visible phenotypes. Experiments involved crossing mutagen-exposed wild-type mice (experimental controls) with mice that were homozygous recessive. In the absence of any mutations in the wild-type mice, all the offspring should be heterozygous and express a wild-type phenotype unless a mutation at a marker gene had occurred. Dr Favor considered that the SLT was the most efficient method currently available for screening F1 populations for expression of newly occurring recessive mutations. He went on to describe highlights in the development of the SLT from 1951, when W.L.Russel (1951) first published results from the SLT using radiation, to 1966 when the first chemical mutagen, triethylenetriamine, was identified. By 1979, two further chemicals, procarbazine and ethylnitrosourea, had been identified and between 1990–1994, all of the seven loci had been cloned, enabling characterization of mutations.
Dr Favor noted that for chemicals tested so far, the majority had been carried out on male germ cells, with few studies in females. He described factors that could affect the resultant mutation rate, such as the target cell population, dose level and use of fractionated doses. The process of spermatogenesis takes 49 days in the mouse and there is considerable variation in sensitivity to mutation induction in the different stages of spermatogenesis due to metabolic changes during this process. Using mutagen-exposed male mice, mutations could be recovered after treatment of dividing cells (spermatogonia), in meiotic prophase, in meiotic divisions and during post-meiotic differentiation (spermiogenesis). In addition, DNA lesion repair can take place through to the mid-spermatid stage and the chromatin structure of a cell changes at the late spermatid stage; all of these factors could be important in affecting the resultant mutation rate. He noted that the method required relatively large numbers of animals. Results for SLT assays using ENU and chlorambucil were presented. To test post-spermatogonial stages adequately, treated mice were sequentially mated with females. Stage specificity was also important for these chemicals. For a chemical mutagen such as ENU in which stem cell spermatogonia are sensitive to mutation induction, following exposure there was a permanent increase in mutation frequency. For a chemical mutagen such as chlorambucil in which post-spermatogonial stages are sensitive to mutation induction, the observed increase in mutation frequency following treatment was temporal. The importance of dose and dose fractionation was also emphasized. Following a single acute treatment with ENU, a dose–response relationship analysis for specific locus mutations in spermatogonia of the mouse indicated that a threshold model provided a better explanation of the results than a linear, linear-quadratic or power dose–response model, and a possible threshold dose of 40 mg/kg was estimated. A series of ENU treatment experiments were carried out using fractionated doses, varying the dose and time intervals between administration. When the individual dose of ENU was much greater than 40 mg/kg, the mutagenic effect was additive regardless of the interval between ENU applications. When the fractionation interval between administration was 168 h (with doses of 2x40, 4x20 and 4x40 mg/kg), there was a significant reduction in the mutation rate, whereas there was no significant reduction when the time interval was 24 h. These observations suggested that the apparent threshold dose–response effect for ENU was due to a saturatable repair process with a threshold of ~40 mg/kg and that the time for recovery of the repair process was >24 h but <168 h. The intermediate fractionation effects when the fractionation interval between dosing was 72 h for 4x40 mg/kg suggested that the repair process in stem cell spermatogonia, which have a long cell cycle of ~192 h, may be dependent upon a particular stage within the cell cycle. However, the observed mutation rate for 10x10 mg/kg with a fractionation interval of 168 h, although reduced, was still higher than the spontaneous specific locus mutation rate. This contradicted the suggestion of a true threshold dose–response effect and Dr Favor emphasized the differences between mathematical modelling of experimental data and the complexities of the biological system being studied.
Mutations recovered in the mouse following ENU treatment were subject to molecular characterization and found to be mostly the result of base pair substitutions at A/T sites. Molecular studies have also characterized an apparent double mutation of the d and se loci on chromosome 9. Possible mechanisms for the d/se double mutation included: deletion of the region; two independent mutations; a single mutation affecting the expression of both loci; loss of heterozygosity (LOH) by gene conversion; LOH by mitotic recombination; LOH by double non-disjunction. Results indicate that d/se double mutations which are homozygous lethal occur by deletion of the region. A d/se double mutation which is homozygous viable was shown to occur via LOH by mitotic recombination.
Professor Colin Arlett (MRC, University of Sussex) described the influence of DNA repair status on mutagen and carcinogen sensitivity in humans. He cited sunlight and ionizing radiation as good examples of well-characterized carcinogens and conditions such as XP, the study of which has greatly increased our understanding in this area.
There is a high instance of early skin cancers in XP individuals; the average age of onset of cutaneous cancers in North Americans is >50, whereas in XP patients it is <10 years. Exposure to the sun is known to be involved because non-exposed regions of the body are not affected. XP patients are hypersensitive to the lethal, mutagenic and carcinogenic action of UV radiation and were found to have a defect in nucleotide excision repair. However, it is not sufficient just to have a defect in repair, and at least seven distinct genes on different chromosomes are known to be involved in many of the steps involved in the carcinogenic response in XP patients. Sunlight is a complete carcinogen and an immunomodulator and consists of electromagnetic radiation (
= 100–400 nm); short wavelengths (UVC) ( = 100–280 nm) react directly with DNA, whereas longer wavelengths ( = 200–400 nm) produce oxidative damage, i.e. 8-oxyguanine, which is removed by a base excision repair mechanism. Experiments showed that XP cells are only sensitive to UV light or DNA-damaging agents that produce large bulky adducts.
Professor Arlett discussed another sun-sensitive syndrome, trichothiodystrophy (TDS), a separate defect in the same DNA repair gene as in XP patients. In TDS patients, this also results in a defect in sulphur metabolism, causing hair to fragment, but unlike XP patients, the skin is not affected. These observations could be explained by other differences between the two syndromes. Unlike XP patients, who are sensitive to suppression of the immune system, TDS individuals have normal immune surveillance following exposure to UV radiation. In experiments with keratinocyte cells, XP patients were much more sensitive to apoptosis, requiring much smaller doses of UV than normal cells. Skin cancer in XP patients could therefore be related to skin type and much quicker `wearing out' of the skin. Thus, the skin cancer risk in DNA repair-defective individuals is correlated with the susceptibility of their cells to radiation.
In the case of ionizing radiation, DNA double-strand breakage (dsb) is an important lesion. Hypersensitivity to ionizing radiation correlates with defects in the repair of dsb linked to A-T mutations and was seen in two autosomal recessive, cancer prone, chromosome fragility syndromes, ataxia telangiectasia (AT) and Nijmegen breakage syndrome. In these syndromes, unlike XP, there is no evidence that cancer proneness is a consequence of hypersensitivity to ionizing radiation. AT cells are believed to have a small defect in the repair of dsb involving impaired checkpoints (between the G1 and S phases). Evidence for this is an elevated level of mutations in circulating T cells of AT patients, who also show defects in immune function and can succumb to leukaemia (a T cell malignancy). Individuals who carry the AT gene are also susceptible to breast cancer. There is also evidence from one patient showing increased chromosome damage of a defective ability to repair dsb and a defect in the ligase 4 gene. Further experiments have investigated chromosome sensitivity and found no differences. Reasons for this could be that sensitivity to chromosome damage and cell lethality are not related or that it could depend on differences in cell type. Professor Arlett concluded that while there is evidence of significant defects in DNA repair, the question still arises about any such variation and any consequences in the normal population. This possibility was being explored in terms of variation in individual sensitivity to ionizing radiation that could have implications in the field of radiotherapy and heterozygosity for the AT gene in breast cancer.
Discussion
Dr I. Purchase (Wilmslow, Cheshire) commented that with ENU, the approximate mutation rate is proportional to the applied dose, with a threshold dose of ~40 mg/kg. It would be valuable to investigate further the apparent threshold using fractionated doses up to and above the threshold level. Dr D. Tweats (GlaxoWellcome, Ware) commented that it would be informative to correlate the level of DNA damage in the testes of test animals with the level of mutations induced by model mutagens in the SLT, e.g. where apparent thresholds in mutations had been observed. Dr Fielder (Department of Health, London) commented on the impracticalities of the SLT in routine chemical testing in view of the large number of animals required for this assay. Professor E. Wright (MRC, Harwell) asked if it would be possible to determine the doubling dose by studying minisatellite changes as this would have the attraction of requiring fewer animals to obtain the same statistical power as studying conventional loci. Dr Favor replied that the statistical power depended upon the total number of mutations recovered. For the highly efficient mutagen ENU, there would be little loss in statistical power. The problem resided in chemical mutagens with lower efficiency. Here numbers were extremely important.
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Metabolic polymorphisms, inherited factors and their study |
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TopJoint COC/COM symposium on...Overview, susceptibility to...Metabolic polymorphisms,...References |
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Dr R. Fielder (Department of Health, London) and Professor Blain (Occupational and Environmental Medicine, Newcastle University) presented an overview summarizing some susceptibility factors such as phase 1 and 2 enzyme polymorphisms, deficiencies in DNA repair and immune response differences. A better understanding of these could be important in the prevention of cancers related to environmental exposures and identify susceptible markers that could be used in population monitoring.
Dr G. Smith (Biomedical Research Centre, Dundee) reviewed metabolic polymorphisms. Genetic susceptibility to cancer could be determined at a number of levels and genetic polymorphisms and the metabolism of xenobiotics was just one of the possible mechanisms which could account for individual susceptibility. In addition to the inheritance of diseases that were strongly predisposed to cancer and the acquisition of mutations in key proto-oncogenes and tumour suppressor genes, susceptibility could also be determined by differences in response to environmental toxins. She gave a brief overview of metabolism in humans, describing phase 1 metabolism as mainly oxidative, reductive or hydrolytic processes that produce substrates for phase 2 conjugations. Much information had come from drug metabolism, i.e. from pharmacogenetics, the genetic basis for individual differences in drug response, which could be related to differences in pharmacokinetics (e.g. drug transport, drug metabolism and disposition or pharmacodynamics).
Dr Smith commented that mammalian enzyme systems had evolved primarily to affect clearance of the complex mixture of chemicals to which we are exposed from the body. The expression of many of these enzymes, including the cytochrome P450 mixed function oxidases, glutathione S-transferase and N-acetyltransferase, is known to exhibit genetic polymorphism, with a variety of phenotypic consequences. Inheritance of an increasing number of allelic variants of these genes has been associated with altered susceptibility to several diseases, the aetiology of which is thought to be influenced by environmental exposure to chemical toxins. In human liver, the predominant P450 is the CYP3A form, although CYP2D6 is responsible for one-quarter to one-third of all drug metabolism reactions. Many alleles of CYP2D6 exist, some of which have poor metabolizing capacity (null or loss of function alleles). PCR techniques have now been used to amplify variant regions of CYP2D6 and these studies could be used to provide an explanation as to why only a proportion of smokers develop lung cancer and if this is related to genotype, i.e. if CYP2D6 activates carcinogens present in cigarette smoke, then poor metabolizers would be protected against lung cancer. In fact, CYP2D6 is known to metabolize a very large number of compounds, including nicotine, but very few are known carcinogens. One compound that is carcinogenic and is metabolized by this enzyme is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a constituent of cigarette smoke. Inheritance of this PM genotype and whether it is a risk factor in lung cancer was studied in lung cancer patients. The results of these studies were highly variable, but a meta-analysis of the data suggested that the PM genotype was slightly protective. CYP1A1, which metabolizes a number of animal carcinogens, including benzo[a]pyrene (also present in cigarette smoke), was also studied in relation to lung cancer. CYP1A1 is polymorphic with a number of allelic variants, e.g. CYP1A1M1 and CYP1A1M2, which have been quite well characterized, and CYP1A1M3 and CYP1A1M4, which have been less well characterized. CYP1A1M1 and CYP1A1M2 are thought to lead to high inducibility. There is a significant positive association of CYP1A1M1 and CYP1A1M2 with lung cancer, although there is no such association with other tobacco-related cancers, e.g. bladder. Glutathione S-transferase (GSTM1) is also highly polymorphic. GSTM1 deletions were found in some individuals and these were associated with an increased risk of lung cancer. Thus, if an individual inherited both the high inducibility form of CYP1A1 and the null form of GSTM1 there would be a significant increase in the odds ratio for cancer risk. GSTP1 is over-expressed in tumour tissue compared with normal tissue and in drug resistance; it is also polymorphic, e.g. the GSTP1b and GSTP1c alleles, which both show different substrate specificities and catalytic activities. Increased risk of testicular and bladder cancer is associated with GSTP1 and in one study it was associated with an increased risk of lung cancer. In skin painting studies with transgenic mice where GSTP1 had been `knocked out', wild-type mice and GSTP1 null mice were treated with benzanthracene. There were no tumours in the wild-type mice, but in the GSTP1 null mice there was a significant increase in the rate of formation and number of tumours recorded. Dr Smith completed her presentation by discussing the implications for cancer susceptibility and asked if there was a genetic basis for inter-individual variation in drug and carcinogen metabolism. To answer this, she presented data on the frequency of some of these genetic polymorphisms; the frequency of CYP2D6 in Europeans is 6–7%, but only 0.05–2% in Chinese. GSTM1 varies across Europe and even within the same populations. She concluded that allele frequency variation accounts for, in part, some individual differences in cancer susceptibility.
Discussion
Professor F. Woods (School of Medicine, Sheffield) asked Dr Smith if she would like to comment on the fact that, in common with other studies of the same general type, the index study linking CYP2D6 to lung cancer overestimated the strength of the association between the poor metabolizer status and that disorder. He also asked whether she thought this phenomenon was due to the nature of the study design and that later studies were better designed. Dr Smith responded by saying that the later studies were of a better design in that phenotyping rather than genotyping had determined the polymorphic status and that the sample groups were larger.
Professor T. Bishop (ICRF Genetic Epidemiology, Leeds) overviewed inherited factors in susceptibility to cancers. He discussed the issue of high and low penetrance genes and how much research to date had focused on a few high risk genes, although it was possible that low penetrance genes (which had a lesser effect on the individual in terms of risk) could affect a far greater proportion of the population.
Clear evidence first came about from a simple examination of the family history of cases where there was a predisposition to breast and ovarian cancer at an early age (e.g. premenopausal breast cancer), i.e. by studying `high risk' families. By tracing inheritance through families, two genes were cloned (BRCA1 and BRCA2). BRCA1 is located on chromosome 17 and BRCA2 on chromosome 13. This has now led to mutation testing in high risk families. There is a high risk of breast cancer in individuals carrying mutations in either of the genes. In addition, BRCA1 is also associated with an increased risk of ovarian cancer. The frequency of BRCA1 mutation was estimated to be 1 in 1000 in the UK population (except in the Ashkenazi population, where the carrier rate was 1–2%). In population based studies, 10% of female breast cancer diagnosed at <35 years (except in Ashkenazi) had the BRCA1 mutation. The cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers is estimated to be close to 70% by the age of 70, made up predominantly of breast cancer, although this estimate varies between families. About 3% of all breast cancer is due to mutations in the BRCA1 gene. It is not known if the same is true for the BRCA2 gene, although mutations in this gene account for 10% of male breast cancer patients. Thus, there is a sizeable population that has an increased risk of breast and ovarian cancer associated with mutations in BRCA1 and BRCA2. This type of study was important in allowing risk assessments within high risk families. There were also `medium risk' families which had 2–4 cases of breast cancer under 50 years of age. In those families where there were two cancer cases, 25% had mutations in either BRCA1 or BRCA2, and where there were three cases, this increased to 40%. Close relatives in such families had an increased cancer risk, but not all such families were explained by mutations in the BRCA1 and BRCA2 genes. With lower penetrance genes, the majority of the increased risk was restricted to sisters of early onset cases. To explain the residual relative risk, lower penetrance genes would have to affect a greater proportion of the population. Such genes were harder to find as it was not possible to follow a family, as for the high penetrance genes. There is also the possibility that low penetrance genes could act through interaction with the environment. Professor Bishop went on to describe epidemiological studies designed to try and detect these low penetrance genes. In case–control studies, cases and matched controls are compared for their genetic make-up and their exposure to risk factors. In addition to the usual matching criteria, the control population have to be matched in terms of genetic heritage and so one solution is that sibling controls be used. The weakness of such studies, however, is poor documentation of exposures, e.g. meat intake, where there is an increased cancer risk for individuals that are fast acetylators but not slow acetylators. Cohort studies involve following a defined population for a given time, measuring their exposure and genetically analysing individuals who develop the end-point. This type of study is, however, expensive and time-consuming. Professor Bishop concluded by saying that there is no proof for the existence of lower penetrance genes for susceptibility, but if they exist they could be more important in terms of public health than high penetrance genes.
Dr D. Scott (Paterson Institute, Manchester) gave a short presentation (pre-publication results) on a recent coded study investigating predisposition to breast cancer. There is accumulating evidence that a wide range of cancer-prone conditions exhibit some degree of cellular radiosensitivity, manifested as an elevated level of induced chromosome damage, particularly if cells are irradiated in the G2 phase of the cell cycle. This is true of AT A-T heterozygotes, which could account for up to 10% of breast cancer cases. In an attempt to detect these amongst breast cancer patients, Scott's group found that 42% (57/135) of breast cancer patients and 6% (6/105) of controls had elevated G2 sensitivity, frequencies considerably higher than expected for A-T heterozygotes. They suggested that other low penetrance genes involved in the processing of DNA damage may also predispose to breast cancer in a considerable proportion of cases. However, the elevated radiosensitivity of breast cancer cases could simply have been a consequence of their disease. To investigate this, the sensitivity of 62 blood relatives of 20 breast cancer patients was determined. Approximately 60% of first degree relatives of patients who were G2-sensitive were also sensitive, whereas the figure was only 7% for relatives of G2-normal cases. This provides evidence of heritability of chromosomal radiosensitivity. Segregation analysis of sensitivity showed that in most families data were consistent with the segregation of a single gene with two alleles showing co-dominant expression. For a few families it was necessary to postulate the existence of a second gene showing additivity with the first. The hypothesis of low penetrance predisposition to breast cancer was considerably strengthened by these findings.
Discussion
Professor D. Davies (Imperial College School of Medicine, London) considered that it was not plausible to link CYP2D6 polymorphism with lung cancer. There was, however, considerable evidence to support an association of NAT2 polymorphism with colorectal cancer. Professor Bishop answered that in the course of epidemiological studies, many different correlations could be identified, some with and some without biological plausibility. Professor Bridges (Sussex) asked Dr Scott if it was possible to derive an estimate of increased risk of breast cancer from these low penetrance genes. Dr Scott said that there is insufficient relevant data at present. Professor Bridges commented that for low penetrance genes, individual increased risks of 2- to 3-fold would not be detected unless population studies were very large. In addition, individuals with an increased risk of 5- to 10-fold for cancer would not be identified in family studies and may not be affected by normal environmental exposure to chemicals, but their exposure under certain conditions could be critical in occupational or clinical situations. Professor Arlett (Sussex) commented that the frequency of high penetrance mutations, e.g. XP and AT, is very small and if considered across the whole population these diseases make a very small contribution to the overall cancer incidence. Professor C. Cooper (Institute of Cancer Research, Sutton) commented that there is a spectrum of susceptibility and that multiple genes are probably involved. Dr Smith commented that the pharmaceutical industry has developed techniques allowing 10 000 genotyping evaluations/day and that such techniques could also be used in non-pharmaceutical situations. Dr S. Venitt (Institute of Cancer Research, Sutton) commented that every effort should be made to reduce exposure to carcinogens and that legislation should never discriminate against susceptible individuals, i.e. the genetic minority.
Dr Fielder (London) summed up the day's proceedings. Professor Parry had highlighted data which showed how a genetic defect in DNA repair influenced sensitivity of cells to spindle inhibition in a somewhat unpredictable way. Dr Favor had reported that chemicals could act as germ cell mutagens and induce mutations in subsequent generations; such chemicals had been tested using the SLT. In terms of risk assessment, mathematical modelling based on data for ENU suggested a possible threshold dose approach, but the data were not completely compatible with this approach and not enough was known to come to any definite conclusions; the prudent assumption by regulators of the absence of a threshold was still warranted. In view of the large number of animals employed, the method was not practical for routine risk assessment of chemicals, although it was useful regarding mechanistic investigations. Professor Arlett provided a molecular basis for increased susceptibility in people with certain syndromes. XP differed in profile from AT, where there was no evidence that cancer proneness was a consequence of hypersensitivity to ionizing radiation. There was no evidence to date that DNA repair defects are important in detecting susceptible cancer-prone subgroups. Dr Smith discussed genes that related polymorphisms to cancer susceptibility. In the case of lung cancer, a number of pharmacogenetic polymorphisms had been studied. There were no associations between increased risk and the CYP2D6 gene, which is highly polymorphic and responsible for metabolism of 25–33% of all drugs. There was, however, a very significant association with increased susceptibility to lung cancer and polymorphism of the CYP1A1 gene. There was an increased odds ratio in individuals with both the CYP1A1 and the GSTM1 null genotype. Professor Bishop discussed inherited predisposition, particularly breast and ovarian cancer. The cumulative risk of breast and ovarian cancer in female BRCA1 mutation carriers was estimated to be close to 70% by the age of 70. In normal populations, the lifetime risk of breast and ovarian cancer was ~8–9 and 3%, respectively, but in carriers of BRCA1 and BRCA2 it was much higher. Population studies suggest that ~3% of breast cancers were due to the BRCA1 gene. Similar comments could be made for bowel cancer, although here there was only limited knowledge on cancer incidence in the UK. With low penetrance genes, it was not possible to identify such genes at the family level, instead, they had to be investigated using population epidemiological studies. However, to date there is no definite proof for the existence of lower penetrance genes which significantly affect susceptibility to cancer. Dr Scott, however, provided some evidence for low penetrance genes and their involvement in breast cancer by measuring chromosome radiosensitivity in breast cancer patients where data from first degree relatives indicated that this sensitivity was inherited.
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Notes |
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* The opinions expressed in this paper represent the opinions of the speakers and do not represent the views or policies of the Department of Health.
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TopJoint COC/COM symposium on...Overview, susceptibility to...Metabolic polymorphisms,...References |
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