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5 June 2001In a paper that is partly a progress report and partly a discussion of policy, Bickerstaff et al describe the activity of the Guy's and St Thomas' Centre for Preimplantation Genetic Diagnosis in London [Bickerstaff, H. et al (2001) Hum Fertil 4, 24-30]. Since the establishment of the Centre, 40 treatment cycles have been carried out, resulting in 12 pregnancies and 15 births so far (with some pregnancies still ongoing). The Centre is licensed by the Human Fertilisation and Embryology Authority to carry out preimplantation genetic diagnosis (PGD) for sex selection to avoid sex-linked disorders, cystic fibrosis, epidermolysis bullosa, spinal muscular atrophy and some chromosomal rearrangements, though referrals have been received for a much wider range of single-gene disorders. Most couples requesting PGD for these conditions have experienced the birth of an affected child, or have a history of spontaneous miscarriages, or have undergone terminations for one or more affected pregancies. Of the 15 babies delivered so far, none have been affected by the condition that was tested for. The authors make a plea that PGD should have a firm place within genetic services. In areas where is is considered to be part of assisted conception services, health authority funding for treatment has sometimes been difficult to obtain, with the result, they say, that "PGD in the UK has progressed very little since ... 1990".
Comment: For commissioners and policy makers with a need to evaluate PGD services in the UK, this paper is a useful adjunct to the recent report by the European Society for Human Reproduction and Embryology (see article in December 2000 newsletter), which describes the combined experience of all European centres offering PGD. The future development of PGD in the UK is likely to be influenced by the outcome of the recent consultation carried out jointly by the HFEA and the Human Genetics Commission.
27 June 2001Only about 5% of cancers are caused by highly-penetrant mutations in single genes, but families affected by these cancers face agonising choices. Often, the only preventive treatment is drastic prophylactic surgery, with all its attendant risks and resulting disabilities. Before the discovery of the genetic mutations causing some of these hereditary cancers, family members had no way of knowing whether they had inherited the disease or not. Now, if a causative mutation can be identified in an affected family member, genetic testing can clarify the risk status of his or her relatives, but deciding on what action to take - regular surveillance or draconian prophylactic surgery - may still be difficult. Huntsman et al, reporting on two families affected by hereditary diffuse gastric cancer, present evidence suggesting that, for this cancer, the presence of the causative mutation may be sufficient to indicate surgery (total gastrectomy) [Huntsman, D.G. et al (2001) N Engl J Med 344, 1904-1909]. They found that in five family members who carried the causative mutation but had no obvious clinical signs of the disease, careful microscopic examination of the stomach after gastrectomy showed that cancer was already developing.
Comment: Hereditary diffuse gastric cancer represents a situation where genetic testing in affected families appears to have a clear benefit in providing a vital early warning to mutation carriers, while sparing unaffected family members further intervention. As pointed out in an editorial by Weitzel and McCahill, early surgery on the basis of presymptomatic genetic testing also appears to be beneficial in some other hereditary cancers, for example multiple endocrine neoplasia and familial adenomatous polyposis. However, in other situations, for example prophylactic mastectomy for carriers of BRCA1 or BRCA2 mutations, the choice between surgery and surveillance may be more finely balanced.
8 June 2001Haemophilia, usually caused by mutations in the X-linked gene encoding the factor VIII protein and affecting about 1 in 5000 males, is thought to be a good candidate for gene therapy. For example, the condition can be improved even by very low levels of factor VIII, and there are no organ-targeting problems, as all that is needed is for the protein to circulate in the bloodstream. Several groups have attempted gene therapy for haemophilia using engineered viruses to introduce the gene into cells, and some success has been reported with this approach. Roth et al have used a different technique: they isolated skin cells from each patient, used an electrical treatment (electroporation) to induce the cells to take up factor VII-encoding DNA, cultured clones of engineered cells and then implanted a suitable clone into the abdominal cavity of the patient [Roth, D.A. et al (2001) N Engl J Med 344, 1735-1742]. The patients were monitored over a period of two years. The trial was a Phase 1 trial to monitor the safety of the treatment, but some subjective measures of efficacy were also recorded: of six patients treated, four experienced some improvement, as assessed by decreased use of factor VIII treatment and a decrease in the frequency of episodes of spontaneous bleeding. The implanted cells produced factor VIII protein at levels of up to 2% of normal for the first few months, but expression of the gene had disappeared after 10 months.
Comment: These results are very preliminary and much more work is needed before it will be clear whether this approach will have a place in the treatment of haemophilia. Some of the outstanding problems are discussed in an editorial by Miller and Stamatoyannopoulos [Miller, D.G. and Stamatoyannopoulos, G. (2001) N Engl J Med 344, 1782-1783]. As well as the need to prolong expression of the factor VIII gene in the transplanted cells, there are questions about the safety of such implants, which could cause inflammatory responses or even become cancerous.
6 June 2001During the last few years it has been discovered that a variant of the gene encoding a cell-surface receptor for certain chemokines (chemical messengers that function in the immune system) is associated with increased resistance to infection by the HIV virus. The variation, known as CCR5D 32, deletes part of the gene encoding the receptor CCR5, with the result that no functional protein is made. In an "early report" published in the Lancet, Fischereder et al present evidence suggesting that this same gene variant decreases the likelihood of kidney transplant rejection [Fischereder, M. et al (2001) Lancet 357, 1758-1761; also see commentary by Strieter and Belperio in the same issue]. Of 576 patients who had received kidney transplants, 21 were homozygous for CCR5D 32; of these, only one experienced rejection of the graft during a follow-up period of 7 years, compared with 78 of the 555 patients who did not carry the CCR5D 32 allele. Transplant rejection is an inflammatory process that involves infiltration of host cells carrying the CCR5 receptor into the graft, a process that would presumably be lessened in people who do not have cells carrying this receptor.
Comment: The approximately 1% of people homozygous for the CCR5D 32 allele appear to suffer no ill effects as a result of lacking the CCR5 protein but they are at decreased risk of a number of immune-system-mediated conditions including rheumatoid arthritis and multiple sclerosis as well as HIV infection and transplant rejection. This suggests that the CCR5 protein might be a safe target for drugs to treat and/or prevent such conditions
1 June 2001Evidence is accumulating that an invidual's risk of disease can be significantly affected by interactions between genetic polymorphisms and environmental factors. A recent example comes from a paper by Xu et al, who have studied the interaction between a polymorphism in the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene and lung cancer risk in smokers and non-smokers [Xu, LL. et al (2001) Cancer Epidemiol Biomarkers Prev 10, 303-210] (Abstract). The NQO1 gene is involved in the detoxification of carcinogens present in cigarette smoke. It has been suggested that individuals carrying the T allele, which encodes an enzyme with low activity, might be at greater risk of lung cancer than those with the normal C allele, but previous studies on the effect of this polymorphism on lung cancer risk have been inconclusive. Comparing 814 lung cancer patients with 1123 controls, Xu et al found that in non-smokers there was no association between the polymorphism and lung cancer risk. However, in smokers there was an association whose strength varied with different durations and intensities of smoking. The relationships between genotype, smoking behaviour and lung cancer risk were complex, but in general the contribution of the NQO1 polymorphism to lung cancer risk was stronger for people with light-to-moderate smoking exposure than in heavy smokers (in whom, presumably, the constant heavy exposure to carcinogens swamps the more subtle effect of NQO1 genotype).
Comment: This study illustrates the need for more studies in which the interactions between genetic and environmental factors in contributing to disease risk are carefully dissected.
15 June 2001The Public Involvement subgroup of the Human Genetics Commission (HGC) recently discussed the development of the Commission's public involvement strategy, which has three overlapping strands: consultation, the media, and information. The Commission has already undertaken several broad, public consultation exercises; members of the group agreed that in addition there should be opportunities for public comment on reports at the draft stage, perhaps at the open HGC meetings, as well targeted consultation with stakeholders on some specific issues. One such stakeholder group will be a Patients' Panel, whose views on key issues will inform the deliberations of the HGC. It was decided that the panel (which will probably be given a more appropriate name) should be as large as practicable, perhaps about 100 members, and that it should consist of people directly affected by genetic disorders, either as patients or as family members or carers. The Panel would work through a combination of meetings and communication by e-mail, a web-based discussion forum, and post.
Collaboration between the HGC and the media may be enhanced by the decision of the BBC to initiate a major project in genetics that will run through late 2001 and 2002 and include an integrated series of television and radio programmes as well as a genetics website and on-line "learning journeys" linked to other educational resources. The HGC will nominate a member to join the steering group for the project. As discussed at the meeting of the Business Committee, the Commission also plans to make its own contribution to genetics education, by publishing key factual information on its website and featuring topics of interest in its newsletter.