In the news

  • Newsletter Edition
The PHG Foundation monthly newsletter features news and views about genetics and genetics research, from a public health perspective. The newsletter is written by staff of the PHG Foundation.

In the news

News story   |   By Dr Philippa Brice   |   Published 22 June 2009

The UK Biotechnology and Biological Sciences Research Council (BBSRC) has launched a consultation on Next Generation Sequencing Technologies, and is seeking comment from “individuals and organisations from the UK’s academic and industrial research community about the potential impacts that these technologies can have on research in biosciences”

Next generation sequencing is a blanket term used to refer to a group of emerging technologies that seem set to transform genomic research. The Human Genome Project stimulated massive technological development in high-throughput DNA sequencing; with the completion of the human genome sequence, the need for rapid, low-cost genome sequencing has intensified. In recent years novel ‘massively parallel’ technological approaches to sequencing have been developed (see previous news), in response to increasing demand and also to funding incentives for the development of efforts to design platforms capable of completing full genome sequences rapidly and at low cost (see previous news); for example, the National Human Genome Research Institute (NHGRI) US$1,000 genome initiative (see press release). 

It is thought that the impact of next-generation sequencing will be revolutionary, enabling unprecedented genomic analysis and opening up whole new avenues of research not previously possible. At the same time, it poses significant challenges; for example, new requirements for massively enlarged data storage, processing and analysis capacity. This is leading various key organisations to take steps to anticipate required changes and policy development; for example, the recently issued recommendations on the future of DNA sequencing at the NHGRI (see previous news). Similarly, the BBSRC intend to use representations as part of a process of strategic development for promoting effective uptake of new sequencing technologies and opportunities for collaborations and ventures within biomedical research. 

Responses are requested by 9th August 2009.

News story   |   By Dr Caroline Wright   |   Published 17 June 2009

The US Centers for Disease Control and Prevention (CDC) have released recommendations for Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions. These guidelines follow the authoritative OECD guidelines for Quality Assurance in Molecular Genetic Testing, published in 2007.

The federal guidelines are aimed at clinicians, public health professionals and those charged with oversight of laboratories in the US. Formulation of the guidance has been stimulated by the rapid increase in genetic testing; the number of heritable diseases for which clinical genetic tests are now available now stands at around 1,300. As genetic research develops, it is anticipated that more and more genetic tests will be used in clinical practice, and already many more are available direct-to-consumer for assessing genetic susceptibility to common complex diseases.

The guidelines state that, although laboratories performing molecular genetic testing are subject to general the Clinical Laboratory Improvements of 1988 (CLIA), further specific guidelines are need to ensure the quality of test performance. These extended recommended practices address the ‘”total testing process (including the preanalytic, analytic, and postanalytic phases)”, as well as issues including informed consent, patient confidentiality, data and specimen storage and access and quality assurance.

For new molecular genetic tests, general principles for determining performance requirements are said to be:

  • review the available scientific studies supporting the test;
  • define the appropriate patient populations;
  • select the appropriate test methodology;
  • establish the analytical performance of the test and quality control procedures
  • ensure that the test results and their implications can be interpreted for an individual patient, and that the limitations of the test are defined and reported.
  • The recommendations recognise the current regulatory gap which exists for laboratory-developed tests (LDTs) as opposed to test kits, and hence emphasise the role of laboratories in providing access to specific information needed by users before making decisions about testing. This information must include the intended use and purpose of a test, indications for testing, method of testing and any limitations of the test. Moreover, laboratories should ensure that the tests they perform are clinically useful and provide documentation regarding clinical validity (sensitivity, specificity and predictive values) and any changes to this as a result of new research.

    Comment: Although the scope of the report is specifically limited to molecular genetic testing for heritable disorders, the authors state that it is intended to be “a resource for users of laboratory services to aid in their use of molecular genetic tests and test results in health assessment and care”. Given the development of numerous genetic tests that purport to predict an individual genetic susceptibility to common complex diseases, it is unclear how applicable the guidelines will be. For instance, it is unclear how laboratories should or could obtain information regarding the clinical validity of a test (including risk models based on multiple genetic markers) without running large trials to establish the clinical performance of that test in an appropriate patient population. Desirable as this would be, in practice it is unlikely to occur. Moreover, a laboratory cannot ensure that the results of a test are interpreted correctly for an individual patient or family, as this falls within the purview of the clinician. Nevertheless, the guidelines represent an important step towards standardising molecular genetic testing procedures and preventing misuse of results in advising patients.

    News story   |   By Dr Philippa Brice   |   Published 16 June 2009

    The European Society of Human Genetics (ESHG) has issued draft recommendations for the regulation of genetic testing for common complex disorders, and is seeking comment from ‘the human genetics community’. The document notes the scope for improved diagnosis, prognosis, management and prevention for common disorders based on emerging genomic knowledge, but contrasts it with the slow delivery of tangible benefits. The dangers of premature and over-hyped genetic susceptibility tests offered direct-to-consumers in potentially undermining public trust in genetic testing for medical purposes are also noted.

    The draft recommendations cover issues surrounding the assessment and regulation of genetic susceptibility testing and screening, and harmonisation of such processes across Europe, as well as various related ethical, legal and social issues. The proposals have been developed by the ESHG Public and Professional Policy Committee, EuroGentest, and the Institute for Prospective Technological Studies, part of the EC Joint Research Centre. They are open for comment until 1st July 2009; a background document is also available.

    The regulation and evaluation of genetic testing is an area of active work for the PHG Foundation, and a formal response to the ESHG consultation will be available shortly.

    News story   |   By Dr Philippa Brice   |   Published 15 June 2009

    A new PHG Foundation report sets out the current UK situation with respect to National Health Service (NHS) provision for patients and families affected by inherited cardiac conditions (ICCs). These are a diverse group of more than fifty genetic disorders affecting the heart, cardiac electrical systems and blood vessels; for example, hypertrophic cardiomyopathy, familial hypercholesterolaemia and long QT Syndrome. It also includes genetic conditions that affect multiple body systems, such as Marfan Syndrome. Taken together, genetic disorders that involve the heart affect around 340,000 people in the UK, although the clinical features and genetic basis of different conditions vary greatly, representing a significant burden of potentially preventable morbidity and sudden premature death.

    Recent rapid progress in the understanding of the underlying genetics of ICCs has made precise genetic diagnosis increasingly feasible; combined with developments in cardiology, working together experts can now provide greatly enhanced diagnosis and clinical management of patients and at-risk relatives. The PHG Foundation funded and led a project to review current technology and clinical services provision for ICCs in the UK. Informed by an expert Working Group (including cardiologists, geneticists, health service commissioners and managers, and representatives from key charities), the project also considered wider issues relevant to the needs of patients and families.

    Heart to Heart: Inherited Cardiovascular Conditions Services sets out findings; service capacity was found to be insufficient to meet current or anticipated future needs, and serious inequalities in provision in different parts of the country were identified. The report sets out the requirements for appropriate specialised services for ICCs, which should include multidisciplinary teams of health professionals, access to the latest forms of testing and clinical investigations and provision of bereavement support and counselling. Increased awareness of these integrated services (for example, among GPs) and co-ordination with voluntary support organisations are also said to be essential.

    The Working Group concluded that every UK cardiac network should ensure that its population has access to specialised expert ICC services for children and adults. Other key recommendations included that cardiac networks and exports should agree on timescales and standards for services, work to ensure that health professionals develop the necessary specialist competences to deliver and maintain these services, and put in place suitable programmes of research and evaluation.

    The report also notes the need for changes to legislation and existing systems to encourage the retention of tissue samples following sudden cardiac death, and for clarification of the responsibility of coroners to family members who may be at risk, allowing investigation of the possibility of an ICC.

    On behalf of the UK Department of Health, Professor Roger Boyle (National Clinical Director for Heart Disease and Stroke) commented: “We welcome this report and will be working closely with the NHS, local healthcare services and charities, including PHG Foundation, to develop these specialist inherited cardiac services and address issues surrounding access" (see press release).

    News story   |   By Dr Philippa Brice   |   Published 12 June 2009
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    News story   |   By Dr Philippa Brice   |   Published 9 June 2009

    Following on from a report earlier this year that some UK hospitals were refusing to allow the harvesting of umbilical cord blood at birth by health professionals licensed by commercial operators (see previous news), the Times newspaper has now reported that parents of babies born in Ireland may sue Irish health authorities for preventing the collection of umbilical cord blood cells at birth. At present, collection can only take place in private hospitals, and cord blood must be stored in tissue banks overseas because there are no public or private Irish cord blood banks.

    Professor Colin McGuckin, stem cell specialist and president of Novus Sanguis, an international research consortium on cord blood and adult stem cell research, is quoted as saying that Ireland was being “left way behind the rest of Europe and the world” and that storing cord blood as a potential future source of therapeutic stem cells for the new baby, whilst not a guaranteed cure, could be “hugely beneficial” (see Times news report). Although tissue-matched stem cells from cord blood can be used for the treatment of various rare diseases, and are considered to hold significant promise for a range of others, the benefits of stem cell therapeutics remain non-proven for most conditions. The argument for storing cord blood is that a precise tissue match would be perfect for future stem cell treatments of the child from whom the sample is taken, should these become available and the child develop a relevant disease in later life.

    The Irish Health Service Executive (HSE) reportedly said that hospitals would harvest cord blood in cases “where consultants identified a risk to a child in later life”, but although in the past there were instances of harvesting at the request of parents for private storage, it had prohibited this practice because of a lack of insurance to cover such staff action. The Clinical Indemnity Sche­me announced last year that it would not cover health professionals for the collection of cord blood for banking by a commercial organization without specific authorisation from the Irish Medicines Board for that hospital to do so, or for the treatment of a named individual organized by the Irish Blood Transfusion service. Private companies that harvest the blood have their own insurance.

    Irish politician and solicitor Alan Shatter (Fine Gael Deputy) said that the HSE was advising hospitals of the insurance implications of collection, but warned there could be a legal liability if the HSE and public hospitals prevented patients from undergoing the process (see Irish Medical News report).

    News story   |   By Dr Sowmiya Moorthie   |   Published 8 June 2009
    The US National Human Genome Research Institute (NHGRI) is currently under-taking a long-range planning process on the future of human genome research (see previous news). As part of this process the NHGRI convened a workshop in March 2009 to discuss the future of large-scale sequencing and has recently released a report of these proceedings. The workshop specifically addressed large-scale sequencing and discussed new projects that will become possible with new sequencing platforms and was aimed at providing guidance on how the NHGRI should continue to support this field over the next five years.

    The Future of DNA sequencing at the National Human Genome Research Institute report outlines a number of general as well as some more specific recommendations which were developed through the course of the workshop. The general recommendations recognised the NHGRI’s unique position within the National Institutes of Health (NIH) and stated that it should maintain a sequencing program that involved large-scale sequencing centres but should also provide opportunities for smaller, more specialized groups to engage in next-generation sequencing projects. In addition, it was also recommended that the NHGRI should address the technical problem of how to finish genomes using new technologies.

    Specific recommendations were made in relation to three main topics:

    • Strategic planning for selecting projects, sample co-ordination, ELSI and consent in the fields of medical sequencing and organismal sequencing
    • Genome Sequencing including human genetics, functional genomics, cancer, the human microbiome and genome evolution and model organisms
    • Downstream issues in relation to data analysis and informatics

    These included recommendations calling on the NHGRI to encourage the creation of sample repositories to ensure the continuous availability of high quality samples and encouraging community education about genome sequencing projects. Recommendation were made in each area of genome sequencing, such as characterisation of sequence variation underlying most common disease with relation to human genetics and implementing deep transcriptome sequencing in the area of functional genomics. With relation to downstream issues, recommendations were made relating to data security and privacy, software and hardware infrastructure and biology using computation.

    Although no programmatic decisions have been made on the basis of these recommendations, the NHGRI will incorporate the findings of this workshop in its decisions. The report states that although the purpose of this workshop was to provide guidance for the NHGRI, as it also collaborates with a number of other international entities such as the Wellcome Trust Sanger institute in the UK, the benefits of large-scale sequencing mentioned in the report will also be shared with international colleagues.

    News story   |   By Alison Hall and Dr Caroline Wright   |   Published 2 June 2009

    The European Society of Human Genetics (ESHG) has published a set of recommendations concerning genetic testing of asymptomatic minors in a clinical context [Eur J Hum Genet (2009) 17: 720-721]. The recommendations follow a period of public consultation (see previous news) and are accompanied by a background paper discussing some of the general considerations with regards to the provision of genetic tests to minors [Borry P et al. Eur J Hum Genet (2009) 17: 711-719].

    Several different testing scenarios are discussed, including genetic testing for adult-onset disorders, childhood-onset disorders and carrier testing. The papers also make an important distinction between presymptomatic testing, where an abnormal test result implies that the disease will almost certainly develop later in life, and predictive testing, where an abnormal result implies a substantial risk that the disease may develop later in life. The guiding principles that were considered when writing the recommendations included the concept of ‘best interests’ of the child, the ability of minors to make informed health care decisions, parents' responsibilities to share genetic information, and the role of clinical geneticists and genetic counsellors in communicating with the family.

    The recommendations state that the primary reason to carry out a genetic test on a minor (who does not have the capacity to consent) should be his or her direct benefit and, the opinion of the minor shall be taken into account in proportion to their degree of maturity. Importantly, due to the potential anxieties and concerns of both parents and children, genetic counselling is always required when considering testing in asymptomatic minors.

    The ESHG make a number of recommendations in relation to presymptomatic and predictive tests. For those conditions with adult-onset, testing is only acceptable if preventative actions cannot be deferred until the child is mature enough to understand the decision and its consequences. Where conditions arise in childhood, the recommendations distinguish between those for which an effective treatment or prevention is available (where the case for testing may be compelling) and those for which there may be no available treatment or prevention (where the harms and benefits of testing may be finely balanced). Importantly, the ESHG does not exclude such testing if a case for psychological or social benefit of the child and his family can be made out.

    Comment: Whilst these recommendations are welcome, they will come as no great surprise to many in the UK, where they largely reflect current best practice for clinical geneticists and genetic counsellors. However, there may be difficulties applying the recommendations where the clinical manifestations of a condition are not well understood, either because it is rare or because there is variability in the age of onset or severity of the condition. There may also be important implications for direct-to-consumer (DTC) genetic testing.

    The UK Human Genetics Commission, which is currently drafting a Common Framework of Principles for DTC genetic tests, has acknowledged that the genetic testing of children is a particularly contentious issue (see BMJ news). There are practical challenges in preventing access to these tests by children via the internet, and arguments about the extent to which genetic information should be treated as exceptional. The Framework will be made available for public consultation before being finalised. It is also notable that in focusing upon test outcomes the ESHG recommendations seem to mandate a more sustained and systematic intervention from clinical genetics professionals.

    Research articles

    Research article   |   By Simon Leese   |   Published 30 June 2009

    A study in Nature [Diskin SJ et al. (2009) Nature 459: 987-991] this month has shown for the first time that a cancer is associated with copy number variation (CNV) in a person’s genome. CNVs are regions of the genome in which the number of repeats of a given sequence vary between individuals. The research looked at neuroblastoma, a cancer of the developing nervous system that typically affects young children and which is often fatal. It is by far the most common cancer to develop in infants.

    The vast majority of neuroblastomas arise sporadically, that is, they occur spontaneously and are not inherited from parents with the disorder. The study however showed that a CNV involving a deletion of a region of chromosome 1 was associated with the disease. This region was not known to contain any genes, but a bioinformatic analysis of the region suggested a previously unknown transcript affecting the expression levels of an NBPF (neuroblastoma breakpoint family) gene that the team showed to be most highly expressed in early neurodevelopment.

    The same research team had previously shown that a number of single nucleotide polymorphisms (SNPs) are associated with neuroblastoma, suggesting that this cancer may arise because of a complex interaction of multiple genetic variants. Lead researcher John Maris has been quoted in an interview as saying: "The genome-wide association field is showing that it is not chance. There actually is a genetic susceptibility, but it takes a perfect storm of inheriting the right mix of these risk factors from Mom and Dad" (see Yahoo! news story).

    Comment: The identification of this genetic variation associated with neuroblastoma may help in the development of new specific genomic treatments for this disease. However, this research is significant not only because it increases our understanding of the causes of neuroblastoma, but also because it potentially indicates an entirely new genetic cause for cancer in general: It had been suspected previously that CNVs could affect cancer susceptibility, but until now there had been no direct evidence to support this.

    Research article   |   By Dr Philippa Brice   |   Published 26 June 2009

    Cancer arises when a series of mutations accumulate that act together to block normal DNA repair (correction of spontaneous mutations) and deregulate normal control over cellular proliferation. A paper in the New England Journal of Medicine reports the results of a phase I clinical trial for a novel cancer therapeutic in patients with inherited BRCA1/2 mutations. Such mutations confer significantly increased susceptibility to a range of cancer sub-types, notably breast cancer (see previous news). This is because there is only one functional BRCA allele present; inactivation of this remaining allele by a non-inherited, spontaneous mutation causes a functional deficit in normal DNA repair. The BRCA1 and BRCA2 molecules are involved in the double-strandedDNA repair pathway; when this is not working properly, then more spontaneous mutations will go uncorrected and the probability of developing a tumour increases.

    Cancer therapeutics attempt to selectively target tumour cells (as opposed to normal cells) for destruction; poor specificity is responsible for the toxic side-effects of chemotherapy. Increased understanding of the genetic basis of different cancers have led to the development of a new generation of molecular targeted therapeutics such as Herceptin, which targets breast cancer cells that over-express the HER2 protein. This latest drug candidate uses an approach termed synthetic lethality. This term refers to a situation where the presence of mutations in each of two separate genes is lethal to a cell, although mutation in either one of those genes is not; for further explanation see accompanying editorial [Iglehart, JD (2009) NEJM June 24,10.1056/NEJMe0903044].

    The new drug candidate, olaparib (AZD2281), inhibits PARP enzymes, essential mediators of single-stranded DNA repair [Fong PC et al. (2009) NEJM June 24, 10.1056/NEJMoa0900212]. Inhibition of PARPs causes the accumulation of single-strand breaks in the DNA, which can in turn lead to double-strand breaks; in normal cells these are repaired, but in BRCA1/2-deficient cells (such as tumour cells in individuals with inherited BRCA1/2 mutations) they are not.

    The researchers recruited a total of 60 patients with advanced forms of different cancer types, 22 of whom were confirmed BRCA1 or BRCA2 mutation carriers and one of whom was a suspected but unconfirmed carrier. All the patients had previously received other forms of chemotherapy. Effective PARP inhibition was detectable in samples of normal and tumour cells from the patients after treatment. The adverse (toxic) effects associated with olaparibwere generally mild compared with normal chemotherapeutics, although there were some cases of dose-limiting toxicity. Anti-tumour activity was observed solely among confirmed or suspected mutation carriers.

    Of the 23 patients in this group, two could not be evaluated (one died from causes unrelated to therapy and another did not receive the full drug dose due to toxicity) and another two showed rapid progression of their tumours, both of which were a type not normally associated with BRCA-carrier status. Of the remaining 19 BRCA carriers, all of whom had ovarian, breast,or prostate cancers, 12 showed clinical benefit from treatment with olaparib. One patient is said to still be in remission more than two years on (see BBC news report)

    The authors postulate that non-responding BRCA mutation carriers might have had differential sensitivity to PARP inhibition due to the exact mutation present or additional genetic or epigenetic changes that restored some BRCA function. However, they conclude that the drug candidate shows promise and suggest that changes are needed in current clinical developmentand registration processes to allow trials of drugs for cancers in different organs, but which chare common genetic origins.

    Comment: These results do not necessarily herald the advent of a new miracle cancer drug; it was a very early-stage, small-scale study, the new drug was not effective in all BRCA mutation carriers, and such individuals represent a very small sub-group of all cancer patients. However, it is an exciting paper because it demonstrates the potential for further development of therapeutics that exploit the unique genetic features of tumours. The point about the potential need to reconsider the trial design and drug approval process for the new generation of molecularly targeted therapies is a good one, since this approach differs so markedly from conventional drug development.

    Research article   |   By Dr Gurdeep Sagoo   |   Published 25 June 2009

    Epidemiological studies may be subject to various types of bias, including publication bias (where studies with statistically significant results are more likely to be published than those without) and time-to-publication bias (where studies with significant results are more likely to be published more quickly than those without). These two forms of bias are well-documented and result in an abundance of spuriously positive study results in the published literature. Ioannidis and Trikalinos [Ioannidis and Trikalinos. (2005) J Clin Epidemiol 58: 543-549] have previously shown that an additional bias, the so-called ‘Proteus phenomenon’, often occurs very early on during the accumulation of scientific evidence, which results in extreme and sometimes contradictory findings. This phenomenon highlights the importance of separate groups performing validation studies in independent data sets, a practice now acknowledged as a prerequisite for convincing epidemiological evidence. As the evidence accumulates and evolves, it should be collated and summarised systematically, with careful control over biases and chance effects, in order to identify true associations and interactions amongst the large pool of false positives (see previous news).

    Nowhere is this problem more apparent than within genetic epidemiology. Reported genetic associations with common complex disease have become numerous in the published medical literature, and because the risks are generally of small magnitude, replication is absolutely essential for weeding out false positive findings and avoiding bias. However, the paucity of established gene-environment interactions to date reflects a widespread failure to incorporate both the genetic and environmental factors in a joint analysis, which weakens the observed association between a true risk factor and the disease and may help to explain the small magnitude of associations often observed thus far.

    A recent systematic review has now disproven one of the few long standing gene-environment interactions [Risch et al. (2009) JAMA 301(23): 2462-2471]. In 2003, an association was established for a “depression gene”, serotonin transporter gene 5-HTTLPR, and depression, showing that in combination with stressful life events, genetic variation in the promoter region of the 5-HTTLPR gene plays a role in predisposition to major depression [Caspi et al. (2003) Science 301(5631): 386-389]. Caspi et al. found that individuals with one or two copies of the short allele appeared to be more prone to depression following a stressful life event (such as sudden unemployment). This finding was particularly attractive because it offered a plausible biological link. Six years on, following several subsequent studies by various study groups, Risch et al. have systematically reviewed the evidence on this topic in order to summarise how the evidence has evolved. Risch et al. identified 26 potentially eligible studies of which 14 met the criteria for a meta-analysis. In their analysis, Risch et al. found no evidence to support the claim that the 5-HTTLPR genotype either alone or in interaction with stressful life events is associated with an elevated risk of depression. Their analysis shows that the stressful life events themselves have a significant association with the risk of depression.

    Comment: This systematic review and meta-analysis highlights two important issues. First, the importance of replication studies conducted using independent data sets by independent groups. Second, as studies are published, the accumulating evidence should be systematically appraised allowing true associations to be identified amongst the ever increasing pool of published associations.

    Research article   |   By Dr Sowmiya Moorthie   |   Published 24 June 2009
    Cervical screening is offered to all women in the UK between the ages of 20 and 60 years, to allow early identification and treatment of pre-cancerous changes. It involves the removal of a small sample of cells from the cervix and their examination by cytology for any abnormalities. Previously, samples for cytological exam were prepared by directly spreading cells onto a glass slide (known as a PAP smear); however, the current method of choice is liquid based cytology (LBC). This involves placing the sampled cells in a pot of liquid, allowing the cells to be better preserved and making the test results more reliable. Cytological results are reported based on the level of cell abnormality and cervical intraepithelial neoplasia (CIN) level.

    The main risk factor for cervical cancer is infection with certain sub-types of human papilloma virus (HPV), and indeed high risk HPV sub-types have been found to be present in almost all cervical cancers. Several studies have shown that human papilloma virus (HPV) testing is more sensitive than cytology in detecting high grade CIN, and could improve the efficacy of screening (see previous news). In the USA, HPV testing is approved for primary screening when co-testing with cytology. However, in the UK a Health Technology Assessment review carried out in 1999 concluded that further research was needed prior to its inclusion in primary screening.

    A Randomised Trial In Screening To Improve Cytology – ARTISTIC trial began in 2001 with the aim of investigating if HPV testing added to the effectiveness of the cervical screening programme. As part of this study, investigators compared the effectiveness of LBC alone or with a HPV co-test in primary screening, and found that co-testing did not identify significantly more cases than LBC alone [Kitchener et al (2009) Lancet Oncol Jun 17 Epub ahead of print]. The trial involved 24 510 eligible women aged between 20 and 64 years in Greater Manchester, three quarters of whom were randomly assigned to a “revealed” group and were told the result of their HPV test, the rest were assigned to a “concealed” group and not told their HPV result.  HPV positive women with negative cytology in the “revealed” group were offered colposcopy (examination of the cervix for abnormal areas) at 12 months and 24 months if they were still HPV positive. All women were invited for a second screening round 3 years later and the pre-cancerous lesion detection rates in the “revealed” and “concealed” groups were compared.

    The study found that when screening involved both LBC and the HPV co-test there was a small but significant reduction in the detection of high grade CIN in the second round of screening. However, when the results of both rounds were combined, the LBC and HPV co-test did not appear to detect significantly more of the high grade CIN than LBC alone. This was similar to results in previous randomised trials comparing conventional cytology along with a HPV co-test and cytology alone.

    The ARTISTIC trial will continue through to a third round of screening six years after enrolment in order to see if HPV screening could extend screening intervals in those women who are cytology and HPV negative and may consequently be at lower risk. The authors cautioned against a stand-alone HPV test for screening as it has low specificity (women under 30 frequently test positive) and a colposcopy for all these women would be impractical. In addition, they state that identification of sub-types will be important in order to identify HPV type-specific persistence and the long-term effects of the HPV16 and HPV18 vaccines, if a stand-alone test is used.

    Comment: Vaccination against infection with HPV 16 or 18, the most common papilloma viruses that can cause cervical cancer, was recently introduced in the UK for girls aged 12-18, and it is expected that this programme will dramatically reduce the future incidence  of disease. Meanwhile, whilst the benefits of HPV testing as part of current screening approaches remain unproven, it seems prudent to continue investigation into the best applications of the test as screening programmes evolve.

    Research article   |   By Dr Caroline Wright   |   Published 18 June 2009

    What’s the connection between Gaucher disease, a rare single gene disorder of metabolism that appears during childhood, and Parkinson’s disease, a common multifactorial disorder of the nervous system that occurs late in life? The answer lies in just a single gene (glucocerebrosidase or GBA), which encodes an enzyme required for lipid metabolism and storage within the lysosome. Numerous pathogenic mutations in this gene have been characterised, which result in Gaucher disease if present in both copies of the gene; these recessive mutations are generally assumed to be relatively harmless to the carrier.


    However, numerous studies have linked pathogenic mutations within GBA with increased susceptibility to Parkinson’s disease. In perhaps the most definitive work to date [Mitsui J et al. (2009) Arch Neurol 66(5):571-6], researchers resequenced the GBA gene in over 500 cases of Parkinson’s disease and matched controls; whilst only 2 of the control subjects had any of the pathogenic mutations associated with Gaucher disease, 50 of the cases were heterozygous for one of 11 mutations in the gene. Having one of these mutations therefore confers a substantial and significant increased risk of developing Parkinson’s disease of nearly 30-fold (OR = 28.0, 95% confidence intervals 7.3-238.3), though individual mutations may be associated with various lower risks [Gan-Or Z et al. (2008) Neurology 70(24):2277-83]. In addition, patients with mutations in GBA were significantly younger at the age of onset of Parkinson’s disease than those without. In contrast, there was no statistically significant association between non-pathogenic mutations in GBA and Parkinson’s disease.


    Comment: This research is important for three different reasons. First, by combining numerous pathogenic mutations in the GBA gene in a relatively large study, the work unifies various earlier and smaller studies linking the gene with Parkinson’s disease.


    Second, it highlights a general paradigm shift from the common disease-common variant hypothesis within human genetics, which underlies the recent plethora of genome-wide association (GWA) studies, to the common disease-rare variant hypothesis. If the majority of genetic risk for common diseases is actually located in rare variants, not common polymorphisms, conducting resequencing analysis of specific susceptibility genes is the logical next step in the hunt for the genetic basis for all common diseases. Adopting such a strategy could therefore be substantially more fruitful than conducting ever larger GWA studies.


    Third, and perhaps most significantly, the work raises serious ethical concerns over carrier screening for Gaucher disease, particularly within the Ashkenazi Jewish population (see previous news). According to the National Gaucher Foundation, the carrier status may be as high as 1 in 15 amongst Jewish people of Eastern European ancestry (and 1 in 100 amongst the general population). The current policy of the UK National Screening Committee is that carrier testing for Gaucher disease should not be offered, as it is treatable and can be relatively mild. However, those who are considering getting tested privately prior to becoming pregnant may now want to think again; a relative risk of ~30 is one of the largest genetic risks known, and may even have predictive ability (though further research is needed here). As Parkinson’s disease has a UK population prevalence of around 1% in the over 65’s (based on data from the Parkinson’s Disease Society), such information could potentially have enormous personal and societal consequences. Additionally, authorities face an even greater challenge – should people who have already had carrier testing be informed of the associated risk of Parkinson’s disease, or not?


    Such ethical conundrums are only likely to increase as more and more genetic susceptibilities are discovered that have relevance to multiple diseases. To date, this has been a relatively small problem, as most of the susceptibilities discovered through GWA studies have been associated with extremely low risks (OR<2) and have very limited predictive ability. However, if the common disease-rare variant hypothesis is correct, we can expect significantly more issues of this nature to surface over the coming years. Policymakers and clinicians will need to bear this in mind when forming national guidance regarding genetic testing and screening.

    Research article   |   By Dr Gurdeep Sagoo   |   Published 11 June 2009

    Numerous biomarkers have been linked to the development of cardiovascular disease. However, given the observational nature of genetic epidemiological research, any given association between a risk factor and disease could be explained by confounding, where the association is explained by a third factor that is associated with the risk factor and the disease, rather than being directly causal. Observed associations may also be due to reverse causation, where the observed relationship is a consequence of the disease rather than the cause. Whether an association is causal or not cannot be resolved definitively from observational epidemiological research.


    The use of randomised control trials (RCTs) in cardiovascular disease has confirmed causal factors such as low-density lipoprotein. Despite being thought of as the most robust study design, RCTs are not always feasible. However, ‘Mendelian randomization’, which relies upon the random assortment of genes from parents to offspring at the time of conception, [Davey Smith G, Ebrahim S. (2009) IJE 32(1):1-22] provides a novel epidemiological research design that is far less susceptible to confounding and excludes reverse causation as a possible non-causal explanation for the observed association [Lawlor DA et al. (2008) Stat Med 27(8): 1133-63]. Because genes are randomly assorted from parents to offspring, this results in non-genetic characteristics that might confound any association being equally distributed amongst the relevant genetic variants, and so allows a randomised comparison between groups of individuals defined by a particular genetic variant. The Mendelian randomization strategy thus helps to clarify whether a causal relationship between a biomarker and a disease exists. A triangle of information is required: specifically, the magnitude of the association between, first, the biomarker and disease, second, the genetic variant and the biomarker, and third, the genetic variant and the disease. The first two associations can be used to estimate the third, which when directly measured can provide an unconfounded assessment of the association between the biomarker and the disease.


    In the recent issue of JAMA, Kamstrup et al. [Kamstrup et al. (2009) JAMA 301(22): 2331-2339] conducted a Mendelian randomization study to assess the role of lipoprotein(a) in myocardial infarction (MI). Several observational studies and meta-analyses have found an association between lipoprotein(a) and MI, with presumptive evidence of a causal relationship. Using the random assortment of genetic variation in the lipoprotein apo(a) gene (LPA), as their randomization, Kamstrup et al. quantify three associations: that between serum lipoprotein(a) levels and MI events; that between LPA gene KIV-2 variants and serum lipoprotein(a) levels; and that between LPA gene KIV-2 variants and MI events.


    Using three independent cohorts from Copenhagen to test the hypothesis that increased levels of lipoprotein(a) cause increased risk of MI, the authors observed an increased risk of MI with elevated levels of lipoprotein(a) in accordance with previous findings. Genotyping of the LPA gene inversely associated the number of KIV-2 repeats with lipoprotein(a) levels. The number of KIV-2 repeats was also found to be inversely associated with risk of MI. Kamstrup et al. were able to demonstrate that a genetically determined doubling of lipoprotein(a) plasma level leads to an increase in risk of MI of 22% (95% confidence intervals: 9% to 37%). These findings were consistently seen in the all three independent cohorts studied, strongly supporting the previous observational studies conducted to date, and are consistent with a causal association of elevated lipoprotein(a) level and increased MI risk.


    Comment: An accompanying editorial by Thanassoulis and O’Donnell [Thanassoulis and O’Donnell (2009) JAMA 301(22): 2386-2388] highlight several considerations that can invalidate the Mendelian randomization study design. Whilst some issues such as confounding due to population stratification can be disregarded due to the homogenous population used in the study, others such as the possible pleiotropic nature (i.e. multiple biological effects) of the KIV-2 genetic variant cannot be ignored, as the KIV-2 variant affects both the lipoprotein(a) plasma level and the lipoprotein(a) isoform size. Although this study provides the strongest evidence to date of lipoprotein as a causal factor for MI, clinical implications remain severely limited. This study also does not investigate whether genetic testing of the LPA gene or measurement of lipoprotein(a) levels can lead to improved MI risk estimation (see previous news). Moreover, no currently recommended medication specifically reduces lipoprotein(a) levels, even if such a test recommended lipid-lowering therapy. Despite these limitations, this successful use of the Mendelian randomization study design by Kamstrup et al. moves lipoprotein(a) from risk marker to causal factor, although the authors agree that the “final proof of causality still requires randomized clinical trials demonstrating reduced MI risk in response to lipoprotein(a)-lowering therapy”.

    Keywords : CHDBiomarkers

    Research article   |   By Dr Philippa Brice   |   Published 4 June 2009

    Testicular cancers - more specifically, testicular germ cell tumours (TGCT) - are the most common cancers in young men. There is evidence that genetic factors may play a more significant role than for many other types of cancer, with the risk of TGCT in the brothers of affected males increased by by 8-12 times (and as much as 75 times for identical twin brothers). 

    A new paper in Nature Genetics reports the identification of genetic factors associated with increased risk of testicular cancer from a small genome-wide association study (GWA). The US researchers compared DNA from 277 white men with TGCT with control DNA from 919 unaffected white men, and identified significant associations with several markers in the KITLG (c-KIT ligand or stem cell factor) gene region on chromosome 12 [Kanetsky PA et al. (2009) Nat Genet. May 31, Epub ahead of print]. A number of additional markers showed lower levels of significance, including some in the region of the SPRY4 (sprouty homolog 4) gene on chromosome 5, which has previously been implicated in the KIT–KITLG signaling pathway. Associations with TGCT were confirmed for selected markers from the KITLG and SPRY4 gene regions in an independent set of 371 TGCT cases and 860 controls. Possession of the higher-risk allele for each marker on chromosome 12 conferred a three-fold increased risk of testicular cancer, whilst homozygosity for the higher-risk allele conferred an overall increase in risk of 4.5-fold. 

    A second paper in the same journal also reports findings from GWAs for TGCT. The UK group looked at DNA from 730 TGCT cases and 1435 controls, and identified markers on several chromosomes. Replication in an independent data set of 571 cases and 1806 controls confirmed significant association between markers on chromosomes 5, 6 and 12 with risk of TGCT [Rapley EA et al. (2009) May 31, Epub ahead of print]. The strongest association was for markers in the KITLG gene region on chromosome 12; homozygosity for a higher-risk allele in this region was reported to confer a six-fold increased risk of testicular cancer, and approximately two-fold for homozygosity at the markers on chromosomes 5 and 6, which lie in the SPRY4 and BAK1gene regions respectively. Expression of the BAK1 gene (which encodes a regulator of apoptosis) in testicular germ cells is repressed by the KITLGKIT pathway. 

    This new testicular cancer susceptibility gene on chromosome 12, KITLG, is highly plausible, given the role of the gene product. Kanestsky et al. note that the KITLG–KIT signalling pathway is involved in various key biological processes including the formation of germ cells (gametes) and male fertility, and that mutations in the KIT gene are common in some forms of testicular tumours. They propose that their findings may reveal some degree of shared genetic basis for TGCT and male infertility (for which an epidemiological association has been reported) and further suggest that the substantially higher observed incidence of TGCT in white males may relate to inherited variation at the KITLG locus, since the KITLG protein is also involved in determining the level of skin pigmentation.

    Comment: The UK researchers are reportedly now seeking to recruit up to 3000 men who have had testicular cancer to participate in the study to identify more genetic risk factors – and, presumably, to validate those already reported in a larger data set and generate more robust estimates of the disease risk associated with each. Referring to the newly identified risk factors, Professor Mike Stratton of the UK Institute of Cancer Research (ICR), where the research took place, commented: “By combining these genetic risks with other known risk factors it may be possible in future to identify men who are at high risk of developing testicular cancer, particularly those who have a brother or father already affected by the disease. This may allow early detection or prevention” (see press release). However, the genetic risk factors identified in the two new papers do not by any means account for all the familial component of testicular cancer risk, and so although information about these risk factors may be able to improve current methods of risk prediction, they would not be very useful without information about other relevant risk factors.

    New reviews and commentaries

    Selected new reviews and commentaries, 1 June 2009

    Reviews & commentaries : by Dr Philippa Brice

    Cystic fibrosis.

    O'Sullivan BP, Freedman SD. Lancet. 2009 Apr 27. 

    Genome-wide association studies: Detecting gene-gene interactions that underlie human diseases.
    Cordell HJ. Nat Rev Genet. 2009 May 12.

    New insights into the aetiology of colorectal cancer from genome-wide association studies
    Tenesa A, Dunlop MG. Nat Rev Genet. 2009 May 12.

    Practical and ethical considerations of noninvasive  prenatal diagnosis

    Benn PA, Chapman AR. JAMA. 2009 May 27;301(20):2154-6.

    A history lesson for stem cells

    Wilson JM. Science. 2009 May 8;324(5928):727-8.

    Genetics of reproductive lifespan.
    Hartge P. Nat Genet. 2009 Jun;41(6):637-8.

    Does the FDA have the authority to trump the Declaration of Helsinki?
    Goodyear MD, Lemmens T, Sprumont D, Tangwa G. BMJ. 2009 Apr 21;338:b1559. doi: 10.1136/bmj.b1559.

    A common genetic mechanism in malignant bone marrow diseases.
    Levine RL, Carroll M. N Engl J Med. 2009 May 28;360(22):2355-7.

    Common cold, uncommon variation.
    Poland GA, Barry MA. N Engl J Med. 2009 May 21;360(21):2245-6.

    The genetics of Parkinson's syndromes: a critical review

    Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C. Curr Opin Genet Dev. 2009 May 4.

    Breaking the gene barrier in schizophrenia

    Horváth S, Mirnics K. Nat Med. 2009 May;15(5):488-90.

    Chaos in the embryo

    Ledbetter DH. Nat Med. 2009 May;15(5):490-1.

    Emergency preparedness for newborn screening and genetic services
    Pass KA, Thoene J, Watson MS. Genet Med. 2009 May 13.

    The Genetics of Crohn's Disease
    Van Limbergen J, Wilson DC, Satsangi J. Annu Rev Genomics Hum Genet. 2009 May 19.

    Developmental biology: Transgenic primate offspring
    Schatten G, Mitalipov S. Nature. 2009 May 28;459(7246):515-6.

    Diabetes: A virus-gene collaboration

    von Herrath M. Nature. 2009 May 28;459(7246):518-9.

    From genes to function: the next challenge to understanding multiple sclerosis
    Fugger L, Friese MA, Bell JI. Nat Rev Immunol. 2009 May 15.

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