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21 November 2003The Bioscience Innovation and Growth Team (BIGT) has reported to government its “…strategic approach to the future of the UK’s bioscience industry.” The UK is currently number two in the world behind the US in the bioscience industry and government and industry leaders want to maintain their competitive advantage against rival countries such as Singapore and Ireland. BIGT was launched in January 2003 to identify the barriers to future bioscience competitiveness and to make recommendations for overcoming those barriers. Their recommendations include creating a National Clinical Trials Agency under the Department of Health to manage clinical trial activities in the NHS and increasing efforts to improve regulatory support for the introduction of innovative medicines. A new Bioscience Leadership Council, made up of industry and stakeholder (NHS, academia) representatives, would facilitate implementing the BIGT’s recommendations. Their ultimate aim is to increase national health while increasing national wealth through a stronger bioscience industry, and, as this is a common goal, it is likely that the government will follow through on many of their recommendations. One suggestion that is not likely to succeed, however, if that of creating new regulations limiting the activities of animal rights activists, who are seen to be inhibiting some clinical research. -

10 November 2003Experts warn that broadly interpreted patents on proteins could prove more obstructive in the future than they have been in the past [Cyranoski (2003) Nature 426, 10-11]. Up until now, patents on large numbers of proteins, unlike genomic sequence, have not caused concern in the scientific community. ‘Protein prospecting’ has traditionally not yielded large rewards, as the process of finding important proteins has been long, labour-intensive and unprofitable, unless the protein could be used as a drug target or as a drug itself, as in the case of erythropoietin (EPO). But now large-scale protein identification is making identifying proteins easier. Projects in the US and Japan have shown that they can quickly determine the structure of thousands of previously unknown proteins, providing many new drug development targets to patent. However, if that patent is broadly written, others may be prevented from working on it, effectively ‘ring-fencing’ the protein. In the past US researchers have relied on a research exemption to avoid this problem, but this might be set to change. In a recent ruling by the Supreme Court, the research exemption was used by Duke University to defend its work on a technology patented by a previous employee. The Supreme Court decided in favour of the employee, stating that the University was not indulging in philosophical inquiry, as allowed by the research exemption, but in active research for gain. If precedent is set and the research exemption is disallowed for those working with patented proteins, work could be hindered. The NIH has funded a study at the National Academy of Sciences to look into the potential impact on research of broadly interpreted patents on proteins and other biological molecules.

13 November 2003The Department of Health has published a consultation document on proposed revisions to the existing regulations made under Section 60 of the Health and Social Care Act 2001. The Patient Information Advisory Group (PIAG) has recommended that the regulations be amended to allow some essential NHS activities that are supported by national databases to process confidential patient information without the need to apply to PIAG. Currently, under the Health Service (Control of Patient Information) Regulations 2002, the Secretary of State can authorise the use confidential patient information without consent for some NHS activities, including medical purposes related to the diagnosis or treatment of neoplasia, such as cancer registries, and activities related to communicable disease and other risks to public health. Others can apply to PIAG for ‘Section 60 support’ but they must prove that, in order to carry out their work, it is not reasonably practicable to obtain consent from the individuals, for example, because the effort would be disproportionate or prohibitive to the research or because consent may be difficult to obtain because of the sensitive nature of the research (for example, research on groups of people who may abuse children). In addition, for medical research, a research ethics committee must have approved the proposed work.

PIAG is recommending that the regulations be amended to give exemptions from needing to apply for Section 60 support to the commissioning of healthcare services, call-up and recall of patients for cancer screening, monitoring performance, and production of statistics on healthcare services and outcomes. These activities require patient information from national databases such as the NHS-Wide Clearing Service and the Hospital Episode Statistics database. PIAG believes that these exemptions are necessary as systems are not in place to adequately anonymise the information in such national databases. Additionally, some research requires access to individual identifiable records.

The closing date for responses to the consultation is 30 January 2004. Views are sought on questions such as whether there are any practical alternatives to those proposed and if more information should be given to the public about the work of these national databases.

18 November 2003The Department of Health has published a model of best practice for the provision of Down's Syndrome screening services by the NHS, which proposes that screening tests should deliver a detection rate of at least 60% (with a false positive rate of 5% or less) by 2004/5, and a detection rate of at least 75% (with a false positive rate of 3% or less) by April 2007. These new benchmarks have been put forward by the UK National Screening Committee (NSC) as a reaction to recent evidence that rates of loss of unaffected fetuses can be dramatically reduced with improved antenatal screening tests (see the Heath Technology Assessment Programme report). Women who receive positive screening results for Down’s can opt for diagnostic testing of the fetus via amniocentesis or chorionic villus sampling; these procedures have an associated miscarriage rate of 1-2%. False positive screening results that incorrectly suggest an increased risk of Down’s syndrome can therefore lead to the loss of some unaffected pregnancies.

Antenatal screening for Down’s syndrome is to be offered to all pregnant women by 2004/2005. The model outlines which forms of screening are acceptable in which circumstances, and aims to implement national provision of the combined test (nuchal translucency measurement by ultrasound plus serum tests) for women requesting first trimester screening and of the optimal integrated test (which combines the results of full first and second trimester screens) for all others by April 2007.The report notes the implications for allocation of resources to the screening programmes, for implementation, training and quality assurance. The NSC is also working to provide improved information resources and counselling services for women to allow informed choices to be made with regard to screening and diagnostic tests. For more information on UK screening for Down’s, see the Down’s syndrome page. –

12 November 2003The US National Human Genome Research Institute (NHGRI) recently announced the formation of a new Social and Behavioral Research Branch (SBRB), due to open in January 2005 as part of the new Social and Behavioral Science Center (see press release). The centre is a National Institutes of Health (NIH) collaborative venture between the NHGRI, National Institute of Mental Health and the Office of Behavioral and Social Sciences Research. Dr Colleen McBride, currently director of the Cancer Prevention, Detection and Control research programme at Duke University in North Carolina, will head both the centre and the SBRB.

The Social and Behavioral Research Branch will seek ways in which to translate information from the human genome into clinical practice, including appropriate interventions to promote health and prevent disease, as well as investigating the ethical, legal, social and policy implications of genomic research. Research will also focus on developing suitable strategies to counsel patients with genetic disorders and their families, including communication of individual risks of developing or passing on a genetic condition. Units within the SBRB will include groups in community and behavioral genetics, health communication and promotion, genetic counselling and ethics and social policy. Underlining the importance of the interdisciplinary approaches to address the complex needs and issues arising from the new genomic era of medicine, Dr McBride commented: "Many perspectives will be needed to translate human genome discoveries into interventions that can address public health problems such as obesity".–

3 November 2003The National Institute for Clinical Excellence, which makes recommendations to the National Health Service on current “best practice” in medicine, has recently published guidance on routine antenatal care for healthy pregnant women. The report recommends that a range of screening tests should be offered to all women, including screening the fetus for Down’s syndrome. A Down’s syndrome screening test providing a detection rate of at least 60% for a false-positive rate of less than 5% should be offered in all centres as soon as possible, according to the guidance, while by April 2007 a test with a detection rate above 75% and a false-positive rate lower than 3% should be universally available. Tests that pass the lower standard include first-trimester measurement of nuchal translucency and first- or second-trimester measurement of three or four biochemical markers in maternal blood. The higher standard is reached only by tests that measure four blood markers or that combine nuchal translucency with at least two blood markers. When offered screening, women should be given information about the characteristics of the test, about the diagnostic tests available to those with a positive test on screening, and about their right to accept or decline screening.

The NICE guidance is in line with the Government’s commitment, in its recent White Paper, to offer antenatal Down’s syndrome screening to all pregnant women by 2004/05, and with policy development by the National Screening Committee, which is currently reviewing the issues involved in moving towards routine use of the higher-quality screening tests. (For further information, see Down’s syndrome page).

28 November 2003The Joint Research Centre (JRC), a European Commission body providing scientific and technical advice to support EU policies, has released a report on quality standards of genetic testing in Europe (Towards quality assurance and harmonisation of genetic testing services in the EU) on quality standards. The number of genetic tests performed yearly in Europe is in excess of 700,000 already, and the practice is expected to grow rapidly in the next few years. The report identifies an absence of unifying policy across Europe on quality, safety and efficacy of genetic testing services, as well as a lack of information on who is performing testing. Participation in EQA (European Quality Assurance) accreditation programmes is fragmentary.

It is proposed that an integrated network should be established throughout Europe (and potentially internationally) to administer an agreed quality assurance system for genetic testing and a central database of participating laboratories, to provide a consistently high performance standard. The authors envisage that this could incorporate existing national EQA schemes, where present, as there are certain advantages to national and region operations, such as the scope for reporting in native languages. The requirement for updated regulatory policies is discussed; current accreditation systems are voluntary. Formal schemes to evaluate the validity, clinical utility and cost-effectiveness of individual tests are proposed. The need for certified reference materials in genetic tests is identified as a key factor in maintaining quality of services, and the development of such materials is suggested. Counselling services offered in the context of genetic testing are highlighted by the report as being of particular importance, but the provision of such services is currently varied. One solution advanced is that laboratories should accept samples only from institutions that are able to provide counselling referrals.

17 November 2003As part of its brief “to provide high quality, equitable laboratory services for patients and their families who require genetic advice, diagnosis and management”, the UK Genetic Testing Network has begun the task of evaluating molecular genetic tests by the criteria of their analytical and clinical sensitivity and specificity, their clinical validity (the ability of the test to detect or predict a disease), and their clinical utility (the benefits and risks of positive and negative test results, the consequences of false positives and false negatives, and whether the test results contributes to decisions about patient management or alters clinical outcome).

Over the summer, participating laboratories in the Network completed “Gene dossier” questionnaires for dozens of DNA tests, documenting not only each test’s performance and usefulness but also the volume of tests provided nationally and locally, the use of each test (diagnosis, prognosis and management, risk assessment, treatment, or presymptomatic testing), the target population, the disease prevalence and gene frequency within that population, and the costs and workload associated with the test.

The UK GTN Steering Group is acting as an evaluation panel, using the gene dossiers as a tool to evaluate both existing and proposed molecular genetic tests, but focussing initially on new tests and on existing tests that appear to warrant review. In a document setting out the procedures and criteria for evaluating tests, it recognises that the final decision as to whether a test is recommended depends on professional judgment; the importance of the evaluation procedure is that it ensures the decision is made “in the context of an open, explicit and transparent process, and … one that has been endorsed by relevant stakeholders”.

12 November 2003Recently the Steering Group of the UK Genetic Testing Network, set up to rationalise and coordinate DNA testing services in the National Health Service with the principal aim of achieving geographical equity for patients, published a directory of tests offered by laboratories participating in the network. Publication of the list follows a review of the clinical validity and utility of existing tests by a panel of clinicians, and assessment of “gene dossiers” prepared by laboratories for new tests that they would like to offer (see news item in November newsletter).

As of May 2003, UKGTN laboratories were offering DNA tests for 253 diseases, testing a total of nearly 70,000 samples annually. These existing tests were given a grade of either 1 or 2. Grade 1 applies to tests that are unequivocally indicated for at least one of five specified categories of clinical need (diagnosis, treatment, prognosis and management, presymptomatic diagnostic screening, genetic risk assessment). Tests given grade 2 are those that the panel considered need further evaluation, usually because the value of DNA testing over other methods such as biochemical analysis needs to be clarified. A second section of the directory lists more than 60 new tests, mostly for rare conditions, whose “gene dossiers” passed scrutiny by the Steering Group of the UKGTN.

The UK GTN has recommended to commissioners and NHS trusts in the UK that the tests listed in the directory should be funded for their local populations so that equity of access can be achieved. However final funding decisions rest with the Primary Care Trusts.

24 November 2003The UK Parliament Science and Technology Committee has announced that they will launch an e-consultation aimed at getting the public’s view on ‘Human Reproductive Technologies and the Law.’ This is part of the Committee’s plan to look at the Human Fertilisation and Embryology Act 1990 with a view to updating it. The Committee has seen recently that the science is outpacing the legal system and is concerned about the Act’s ability to withstand legal challenges, based on court cases involving the HFEA’s ability to license research using cloned embryos and pre-implantation genetic diagnosis with tissue typing. As the introduction of new technologies is only set to continue, the committee wants to know if the public wants strict regulations on technologies or to be given the ability to determine for themselves and their families what is best. The Hansard Society, an independent, non-partisan educational charity, will oversee the web-based consultation. It will continue for six weeks, beginning from mid-January, at www.parliament.net (on-line from mid-December).

6 November 2003The UK Parliament Science and Technology Committee has announced that it will review the Human Fertilisation and Embryology Act 1990, in response the refusal of the Government to update the Act to take account of new technologies. The Human Fertilisation and Embryology Authority, the agency tasked with regulating reproductive technologies as covered under the Act, has been challenged in court on several issues recently, such as preimplantation genetic diagnosis and consent issues related to frozen embryos, indicating that the Act needs to be updated. However, the reluctance of the Government to make these changes has moved the Committee to take this action. The Committee intends to consult widely on the issues involved, including an ‘e-consultation', in order to inform its decisions. Further details on the consultation process will be announced in the near future.

6 November 2003An article in The Lancet [Ntzani and Ioannidis (2003) Lancet 362, 1439-1444] reports a systematic assessment of genetic profiling studies of malignant cancers using DNA microarrays, systems that enable the rapid and simultaneous analysis of thousands DNA sequences. Cancer profiling examines patterns of gene expression in tumour cells to identify characteristic ‘molecular signatures’ associated with the sub-type of cancer, and with certain clinical outcomes such as response to treatment, recovery, metastasis or death. It is often difficult to identify the precise sub-type of cancer present using normal clinical indicators, but this information is highly relevant to prognosis and treatment. The hope is that DNA microarray technology will permit improved diagnosis and prognosis of cancers and identification of the most appropriate therapy for individual tumours, with a view to providing optimal treatment.

The authors looked at published studies on genetic profiling of cancers, around a third of which included relevant data on major clinical outcomes. They analysed the ability of gene profiling to accurately predict outcome for the patients in the studies, and compared this with standard prognostic procedures based on clinical and pathological variables. The need for validation of gene profiling studies – and in particular, validation using independent data sets – is emphasised by the report as being critical to confirm proposed molecular profiles and prognostic indicators. Three-quarters of the studies were found to have omitted any form of validation of their findings. The predictive performance of the prognostic gene expression profiles was variable, with smaller studies showing generally better concordance with actual clinical outcomes. Larger sample sizes are proposed to be necessary for future confirmatory studies, along with adjustment for known predictors of outcome (such as size and stage of cancers).

Comment: DNA microarrays have been hailed as a technology with the potential to revolutionise cancer treatment. In order to realize this promise, it will be necessary to produce reliable genetic profiles for different forms of cancer that can be used in a clinical setting. This paper makes a series of recommendations intended to facilitate the development of prognostic tools from microarray data. A commentary on the report [Winegarden (2003) Lancet 362, 1428] affirms the authors’ call for standardisation of methods (including validation techniques) as a prerequisite for generating a body of information sufficient to permit translation into clinical benefits for cancer patients.

14 November 2003The lifetime risk of breast cancer for women in the general population is over 10%, and the risk of ovarian cancer is 1.8%. However, women who inherit mutations in the BRCA1 and BRCA2 genes have a much higher risk of developing breast and ovarian cancer. These risks are also known as the penetrance of BRCA1 and BRCA2 mutations – penetrance being the degree to which a genetic trait is expressed. There has been considerable debate about the possibility that genetic, environmental or lifestyle factors can modify the risk of disease in BRCA1/2 mutation carriers. If this were the case, it might be expected that cancer risks for mutation carriers in multiple case families would be higher than those for mutation carriers with minimal or no family history of disease. Indeed, early estimates of disease risk based on mutation carriers ascertained irrespective of family history were somewhat lower than estimates based on multi-case families, though the confidence limits for these estimates were wide. More recently a meta-analysis of 22 studies of mutation testing of cases unselected for family history provided more precise estimates of risk. This study confirmed that penetrance estimates derived from multi-case families were somewhat higher than those from unselected case-series.

Three BRCA1 and BRCA2 mutant alleles are common in the Ashkenazi Jewish population. Other, family-specific mutations, are rare in the Ashkenazim, as in other populations. A new study in New York reported in Science [King, M. et al. (2003) Science 302, 643-646] examined the families of just over 1000 Jewish women with breast cancer determine the risk of cancer in female relatives with inherited BRCA1 and BRCA2 mutations. Around 10% of the women diagnosed with breast cancer were found to have BRCA1 or BRCA2 mutations (index case mutation carriers). All the female relatives of index mutation carriers were then contacted and tested for the presence of the relevant mutation enabling direct estimates of cancer risks to be derived, unlike earlier studies that have relied on computed probability of mutation status in relatives in order to estimate penetrance. The risk of breast cancer by age 70 was 71% (95%CI 63-79%) for female relatives with either a BRCA1 or a BRCA2 mutation. When analysed separately risks were similar for BRCA1 and BRCA2 mutation carriers at age 70, though BRCA2 carrier risks were somewhat lower at early ages. The risk of ovarian cancer associated with the two mutations differed, however: 46% for women with BRCA1 mutations but only 17% for BRCA2 mutation carriers by age 70. Only half of the index case mutation carriers had family histories of breast or ovarian cancer among mothers, sisters, grandmothers, or aunts. However, the risk of cancer among female carriers of BRCA1/2 mutations from low-incidence families was found to be the same as the risk for those from high-incidence families. That is, low family incidence does not indicate low risk; rather, it can arise from circumstances such as small family size or a greater proportion of male relatives in the family. An article accompanying the King et al. study [Levy-Lahad and Plon (2003) Science 302, 574-575] comments that this sort of result demonstrates the benefits of direct molecular analysis of relatives (as opposed to simply recording family history).

The authors also found that non-genetic factors influence the penetrance of these mutations. Physical exercise and lack of obesity in adolescence were associated with significantly later onset of breast cancer. Moreover, risk of breast cancer for BRCA1/2 carriers was found to be higher in women born after 1940 than those born before it, suggesting that lifestyle factors associated with more recent birth cohorts are associated with increase risk in mutation carriers. An important corollary of these findings is that the risk estimates presented in detail describe the average risks across the range of exposure to non-genetic risk factors in the cohort of mutation carriers used to estimate these risks.

Comment: This report contributes additional data to the controversy over the magnitude of breast and ovarian cancer risk conferred by mutations in BRCA1/2, which are broadly in line with previously published data. The magnitude of the breast and ovarian cancer risks were slightly higher than the meta-analysis, though there is substantial overlap in the confidence intervals. Furthermore the different patterns of risk in BRCA1 and BRCA2 mutation carriers were similar - lower breast cancer risks at earlier ages and lower ovarian cancer risks at all ages in BRCA2 carriers. The findings also support previous studies that have found evidence that lifestyle factors modify risk. The observed effect of birth cohort is similar to that described in the meta-analysis. Thus, differences in average risk estimates between studies could easily be explained by differences in prevalence of non-genetic risk factors between different studies. This may be important for genetic medicine in general and for breast and ovarian cancer research in particular. Levy-Lahad and Plon call for further study into non-genetic effects on expression of disease susceptibility genes, which would vary considerably across the general population.

[Authored in consultation with Dr Paul Pharaoh]

27 November 2003A team led by Cambridge researchers has identified a novel gene product, EMSY, which is reported to link the BRCA2 pathway of tumorigenesis to sporadic breast and ovarian cancer. Mutations in the genes BRCA1 and BRCA2 are known to account f