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 31 March 2010

The UK Government Department for Business, Innovation and Skills has five expert groups established to inform science strategy in different key areas: Science for All (making science relevant to everyday life and encouraging public engagement); Science and the Media; Science and Learning; Science for Careers; and Science and Trust. The Science and Trust Expert Group is supposed to promote social responsibility and ethics in science, consider the societal and ethical implications of developments, and provide ‘independent evaluation of activities so that societal issues are reflected in transparent decision making by Government and business’.


Earlier this month the group released a new report, Starting a National Conversation about Good Science)., following an earlier consultation on Science and Society. The report encourages the public to have a healthy degree of scepticism with respect to science and makes recommendations with a view to Enhancing society’s capabilities to make better informed judgements about sciences and their uses in order to ensure that the 'licence to operate' is socially robust’ (see press release).


Importantly, the report also calls for more discussion of risk and uncertainty in science, for more education about ethical behaviour as part of scientific training, and for scientists to work more closely with ‘social scientists and other research professionals in developing and using good evaluation practice’.

News story   |   By Dr Philippa Brice   |   Published 30 March 2010

Prominent UK academic lawyer Baroness Deech, who chaired the Human Fertilisation and Embryology Authority from 1994 to 2002, has caused controversy in the genetics community following media reports of a recent family law lecture she gave on cousin marriages.

An advance interview in the Times newspaper reported that one element of the lecture would be a call for a campaign to highlight the risks and the preventative measures” about the genetic consequences of consanguineous marriages, citing the example of screening for Tay-Sachs disease in Jewish communities, information from which is sometimes used in arranging marriages (see Tay Sachs Disease Carrier Screening for more information). The paper said that Baroness Deech would also propose in vitro fertilisation (IVF) and prenatal genetic diagnosis (PGD) for married cousins planning to have children – although in fact this was suggested only for couples with a family history of genetic disease.

Comment: There are some major flaws with the substance of this article as reported. Recessive genetic disorders affect children whose parents are both carriers of a causative mutation for that disease. Many healthy people carry such mutations, but it is rare for two parents to each pass on a mutation associated with the same disease, so that a child is affected. For example, the carrier rate in the general UK population for the disease cystic fibrosis (one of the most common genetic diseases) is around 1 in 25, or about 2 million, but the birth rate of children with cystic fibrosis is only around 1 in 2400, or about 240 each year (see Cystic Fibrosis Trust)

Recessive genetic disorders can affect any family, although their frequency may vary in different ethnic groups. Marriages between close relatives do significantly increase the probability that children will be affected by a recessive genetic disorder – but only if both cousins are carriers. Therefore, whilst increased awareness of the possibility of genetic disorders in communities where consanguineous marriages are common (including among health professionals) is a very good idea, the article (as opposed to the original speech) gives a false and potentially alarming impression of the true risks.

News story   |   By Dr Philippa Brice   |   Published 30 March 2010

In the latest legal reversal, a US judge has ruled that two patents held by Myriad Genetics for the diagnosis of mutations in the BRCA1 and BRCA2 genes associated with inherited predisposition to breast-ovarian cancer syndrome are invalid.

Legal action was taken against the company along with joint patent holders the University of Utah Research Foundation and the US Patent and Trademark Office last year by the American Civil Liberties Union and the Public Patent Foundation (see previous news). They claimed that the patents, which grant exclusive rights over testing, and for which the patent holders had consistently refused to grant licences to allow any other parties to perform testing, harm at-risk women, for whom it makes accessing testing more difficult and expensive, and stifle research.

District Judge Robert Sweet reportedly said that he was invalidating the patents of the basis that the existence of DNA in an isolated form did not affect the fundamental natural state of or information encoded by that DNA in the human body – that is, isolated DNA is not substantially different from native DNA and hence cannot be patented (see Washington Post article).

Comment: Although this judgement is potentially very significant, the contentious issue of human gene patenting is by no means resolved, since yet another legal counter-move will almost inevitably follow. Cheaper access to BRCA testing in the US is unlikely to become available in the near future. However, it represents another indication that the current system of patenting that may be effective for traditional medical offerings such as pharmaceuticals is not effective for the post-genomic era. Efforts to find a compromise whereby companies can receive a financial return for investment in research without simultaneously stifling further research to the detriment of people’s health must continue.

For more detailed analysis of this judgment, see the Genomics Law Report.

News story   |   By Dr Caroline Wright   |   Published 31 March 2010

The Organisation for Economic Co-operation and Development (OECD) has produced special issue of its Journal, entitled "Agricultural and health biotechnologies: Building blocks of the bioeconomy”, which aims to provide evidence-based projections on the development of biotechnologies in agriculture and health. The Human Heath Biotechnologies to 2015 report summarises developments in health therapies (including biopharmaceuticals and gene therapy), diagnostics and bioinformatics (including genetic tests), functional foods and nutriceuticals, as well as medical devices.

The OECD estimates that the total in vitro diagnostics market was worth US$27.6 billion in 2004, of which molecular diagnostics (such as DNA-based tests) accounted for 5%. Of particular interest, the Report identifies numerous genetic tests using different genotyping methods, as well as providing a brief discussion of new DNA sequencing technologies. Moreover, it suggests that, following a substantial increase in the number of genetic tests available over the last 20 years primarily for rare disorders, “genetic testing is likely to shift from identifying single genetic mutations to tests for multiple genes… these tests could include microarray technologies to help identify multiple gene variations.” The Report also reviews the current status of pharmacogenetics, noting three specific applications – identification of responders to targeted treatments, establishing appropriate dosages for responders, and identification of those susceptible to adverse drug reactions – and predicts a rapid increase in the number of pharmacogenetic treatments and companion diagnostics over the coming years, which may serve to substantially shorten the drug development pipeline.

News story   |   By Dr Caroline Wright   |   Published 20 March 2010

The use of genetic testing to predict how different individuals will respond to particular drugs is one of the major areas where genomics is expected to yield enormous clinical benefits across a range of diseases (see previous news). Understanding how an individual’s response to medication may be affected by their genetic sequence (pharmacogenetics) could improve dosing, reduce adverse drug reactions and allow targeting of drugs.

One of the first drugs where pharmacogenetic information could be useful for judging the best dosage to prescribe to patients is warfarin, the world’s most popular anti-coagulant, which in addition to preventing blood clots may also cause serious bleeding events in a large number of patients. Common variants in just two genes (CYP2C9 and VKORC1) explain most of the variation in drug response, so it has been suggested that genetic testing could be used to determine whether an individual is a slow or fast metaboliser and hence help physicians decide what dosage to prescribe . However, to date, although there is good evidence for the clinical validity for this test, evidence of improved clinical outcomes as a result of testing has been lacking (see previous news).

The results of a trial designed to test whether genotyping reduced the chance of warfarin patients being hospitalised were announced this week at the American College of Cardiology annual Meeting. The hospitalisation rates of nearly 900 new warfarin patients with genotyping results were compared with rates for a historical control group of similar patients without genotyping. The results suggest that genotyping warfarin patients resulted in a 30% reduction in hospitalisations. Dr Robert Epstein of the Medco Research Institute in New Jersey, said, "Our study shows that genetic testing is a tool clinicians can use to more accurately predict the best warfarin dose early on. Patients may get to a stable dose more quickly and therefore have a lower risk of negative outcomes" (reported in The Heart).

Comment: This study provides strong evidence of clinical utility for using genetic testing to determine the best dosage of warfarin. If it also proves to be cost-effective versus using traditional clinical methods for adjusting warfarin dosage, the UK NHS may have to follow the US FDA’s lead in recommending (see previous news) and ultimately implementing genotyping for new warfarin patients.

Keywords : CHDstrokePharmacogenetics

News story   |   By Dr Caroline Wright   |   Published 19 March 2010

The US National Institutes of Health (NIH) has announced that is creating a “public database that researchers, consumers, health care providers, and others can search for information submitted voluntarily by genetic test providers” (see press release). The aim of the Genetic Testing Registry (GTR) is to improve the levels of information accessible to consumers about the availability, validity and usefulness of genetic tests. Although the exact scope of the GTR will no doubt develop, it will initially focus on tests that “involve an analysis of human chromosomes, deoxyribonucleic acid, ribonucleic acid, genes and/or gene products (e.g. enzymes and other types of proteins), which is predominantly used to detect heritable or somatic mutations, genotypes, or phenotypes related to disease and health.”

The NIH states that over 1,600 genetic tests are currently available to patients and consumers, but there is no single database collating information about them. The GTR should provide a trustworthy resource for consumers and medical professionals and encourage test providers to be more transparent about the evidence associated with their tests. In addition, the test data will be integrated with information in other genetic, scientific, and medical databases to facilitate translation of research findings into practice. As part of the development process, the NIH will involve numerous stakeholders and federal regulatory bodies to determine the best way to develop and present the GTR.

Comment: Irrespective of the ongoing debate surrounding the legitimacy of consumer genetic testing, there is an urgent global need to construct an accessible evidence base for all diagnostic tests, to encourage accuracy, reliably, validity and effectiveness, and to ensure that any claims are consistent with the scientific evidence. There is currently no systematic evidence base for diagnostic tests, neither those used by clinicians nor those available to the public; furthermore, unlike pharmaceuticals, there is no agreed mechanisms for generating or assessing evidence about diagnostic tests. Simply achieving transparency about the level of evidence associated with novel tests is the first step towards redressing this balance, and would provide both health care providers and consumers with the necessary tools and information to make informed decisions.

In the UK, the PHG Foundation has repeatedly highlighted the need for such an evidence base (see our Diagnostics Summit report). In the US, a mandatory registry of laboratory tests was also proposed several years ago by the Secretary’s Advisory Committee on Genetics, Health and Society (see previous news); however, when proposals for implementation were developed last year by the Genetics and Public Policy Centre (see previous news), the registry became limited to genetic tests. Although this is a clear example of genetic exceptionalism, the GTR may represent an important first step towards realising these goals, and could ultimately inform the development of a test registry with a much wider remit and greater regulatory clout. Moreover, while the aims of the GTR are certainly laudable, it remains to be seen whether a voluntary database will be effective; nonetheless, it may be the only option given the global nature of both genomics research and the genetic testing market. In fact, the voluntary nature of the database may itself provide an indication of the quality of service offered by different companies, and reputable companies will finally be able to distinguish themselves from those selling the genetic equivalent of ‘snake oil’.

News story   |   By Dr Philippa Brice   |   Published 18 March 2010

The annual report of the Chief Medical Officer for 2009, released this week, highlights the issue of rare diseases. These diseases, many of which are genetic in origin, are typically chronic, progressive conditions that begin in childhood, including neurological, muscular, heart and metabolic disorders.

Under the title ‘Rare is common’, CMO Sir Liam Donaldson notes that whilst individually rare (affecting fewer than five in every 10,000 people), the large number of different rare diseases means that collectively they are significant – affecting one in 17 people (around 3 million) in England alone, and more than 30 million in Europe. In particular, the report highlights the problems encountered by affected children and adults in obtaining an accurate diagnosis, and accessing appropriate, specialist health services to help them manage their conditions.

The report calls for appointment of a National Clinical Director to oversee treatment and surveillance of rare diseases; improved coordination of specialist services via a strengthened network of reference centres; more funding for research and international cooperation to share information about these conditions; training of additional specialist health professionals to meet future needs; and raised public and professional awareness about rare diseases.

Speaking in The Times newspaper, Sir Liam said: “These are the Cinderella conditions...This is about patchy and fragmented services, poor co-ordination and lack of clinical awareness about the diagnosis. It’s not just poverty of access, but poverty of visibility and representation”.

In a letter also published in The Times, PHG Foundation Programme Director Dr Hilary Burton welcomed Sir Liam’s focus on rare diseases and noted that in fact in many cases: “diagnostic tests are already available, and there is interest in expanding the conditions currently included in the panel of diseases for which newborn babies receive routine screening”.

Currently in the UK, newborns receive screening for phenylketonuria (PKU), congenital hypothyroidism, sickle cell disorders, cystic fibrosis and medium-chain acyl-CoA dehydrogenase deficiency (MCADD). The purpose of early screening for such conditions is where early diagnosis can improve health outcomes for the affected child, in some cases with profound effect – for example, prompt dietary control of PKU prevents irreversible mental retardation.

The UK Department of Health has also been considering plans to speed access to new therapeutics for patients with rare diseases (see previous news).

News story   |   By Dr Philippa Brice   |   Published 15 March 2010

A new partnership between major global pharmaceutical companies Eli Lilly, Merck and Pfizer is to create a non-profit Asian Cancer Research Group (ACRG) to investigate the most common cancers in Asia such as lung and gastric (stomach) cancers.


The aim is to create a publicly available genomic and pharmacogenomic database in Singapore, initially using data from around 2,000 lung and gastric cancer tissue samples linked to clinical information; these are two of the most common forms of cancer in Asia. It is hoped that collaborative partnerships will support creation of the database, and that it will be used to analyse genomic features of the cancers and identify opportunities for new drugs and other therapeutics to treat them.


The venture highlights the need for population-specific research and therapeutics for some diseases; for example, gastric cancer is relatively rare in the West but a major cause of death in Asia. Similarly, a significant proportion of Asian lung cancer patients possess an EGFR mutation rare among Western patients but whcih can result in poor responsiveness to standard drug treatments. Neil Gibson, Chief Scientific Officer of Pfizer’s oncology research unit said: “Environmental and genetic factors are believed to underlie the dramatic differences in the molecular subtypes and incidence of cancers in Asia and other parts of the world”, noting that such cancers represent a major health burden in this part of the world (see press release).

News story   |   By Dr Philippa Brice   |   Published 9 March 2010

The UK Human Tissue Authority (HTA) has issued an official warning that unlawful collections of umbilical cord blood have been taking place in the UK, and that such instances ‘may compromise safety and quality standards’ (see press release).

Cord blood banking is growing in popularity in the UK; last year some 15,000 collections were made of which around one quarter were for public, charitable or research recipients (see BBC news) such as to the NHS Cord Blood Bank, whilst the remainder were via commercial providers who charge £1000-2000 for collection and storage of the samples. Whilst stem cells from cord blood can currently be used for treatment for a few serious diseases such as leukaemia, private companies typically market their services to parents on the basis that stem cells will be the key to successful treatment of a whole range of diseases in the near future.

Banking has been regulated in the UK by the HTA since 2008 (see previous news); collections may only be made under an HTA licence, requiring suitably trained staff. This is to ensure not only the quality, safety and traceability of the sample obtained, but also to ensure that collection procedures do not divert key medical attention from either the mother or baby, which has caused concern in the past (see previous news). 

Now the HTA is contacting more than 150 organisations to warn them about the dangers of unlawful cord blood collection, whether by parents themselves or by unlicensed medical staff. They are also urging parents who wish to chose cord blood banking (for example, via a commercial provider) to make sure that arrangements for proper collection are made well in advance, to avoid midwives or other unlicensed medical professionals being put under pressure by parents to make illegal collections.

News story   |   By Dr Philippa Brice   |   Published 8 March 2010

The PHG Foundation has joined many other eminent UK-based organisations in signing up to the National Petition for Libel Reform seeking amendment of English libel law. Libel is when published or broadcast material claims or implies something about an individual or group that portrays them in a negative light, usually falsely.


The unusual legal position was highlighted in 2009 when the science writer Simon Singh was sued for libel by the British Chiropractic Association (BCA) after they took exception to comments made in a piece he wrote in the Guardian newspaper (see news article for more details) saying that BCA claims that chiropracty could treat a range of conditions such as ear infections and asthma were ‘bogus’ and unsupported by adequate scientific evidence. Of note, the BCA took legal action not against the newspaper but against the writer personally. Most individuals could not begin to defend such a case due to the very high expense of legal action, though in fact Simon Singh had both the means and the will to do so.


However, the petition was not solely occasioned by this dispute. Other cases are causing similar concern in the scientific and medical communities, particularly the phenomenon of large companies or associations choosing to take legal action for libel against individuals unlikely to be able to defend themselves. Another prominent example is that of consultant cardiologist Dr Peter Wilmshurst who is being sued by NMT Medical, after he suggested that one of their products (for which he was involved in a clinical trial) was flawed (see Times article).


It is feared that English libel law may be making it possible for financially well endowed groups to effectively silence scientific dissent about their own claims. The petition to reform the law to protect normal scientific debate has been organised by the charity Sense About Science; Managing Director Tracey Brown comments: Libel laws are not just a Fleet Street issue. We have heard from scientists, campaigners, writers, academics and patients that their discussions and publications are being shut down by the threat of libel action. Critical and open debates are vital in medicine and the public are badly missing out without them”.

Research articles

Research article   |   By Dr Gurdeep Sagoo   |   Published 30 March 2010

In the UK, lung cancer is the second most common diagnosed cancer and the most common cause of cancer death accounting for more than 1 in 5 cancer-related deaths (according to Cancer Research UK). Although smoking is the single largest risk factor for lung cancer, and causes almost 90% of lung cancer deaths, around a quarter of lung cancer cases worldwide have no history of smoking.

Using a “four-stage” case-control study design, Li et al. have investigated the genetic basis for lung cancer in non-smokers [Li et al. Lancet Oncol (2010) doi.10.1016/S1470-2045(10)70042-5]. The first stage used a genome-wide association study design to genotype more than 300,000 SNPs across the genomes of 754 ‘never smokers’, i.e. people who have smoked less than 100 cigarettes during their lifetime, which yielded 44 SNPs for further investigation. In order to validate these initial findings, the second stage involved genotyping these 44 SNPs in a further almost 1000 never smokers from two different study populations. Combining the data from all three study populations strengthened the association observed for two SNPs in complete linkage disequilibrium (rs2352028 and rs2352029) on chromosome 13. Based on the third stage results, just rs2352028 was genotyped in a fourth study population comprising of 530 never smokers, and when all four study populations were combined in a meta-analysis, the association between rs2352028 and lung cancer in never smokers produced an odds ratio of 1.46 (95% CI 1.26-1.70; p=5.94 x 10-6).

In the fourth stage of the study authors investigation, they identified 36 genes surrounding the 44 top SNP results from the first stage, and conducted a gene expression study involving normal lung tissue samples from 70 cases. Only the two replicated SNPs (rs2352028 and rs2352029) showed a strong association with the expression level of a nearby gene (GPC5). Individuals with a high risk allele at rs2352028 had a substantially lower expression of GPC5 than those individuals with the more common allele. When looking at only adenocarcinoma (a clinical subtype of lung cancer) cells, the GPC5 expression levels were half that of normal lung tissue. The authors therefore speculate that the two genetic variants on chromosome 13 (located within intron 5 of the GPC5 gene) might affect regulation of GPC5 expression.

Comment: Very little is known about the molecular genetics of lung cancer in non-smokers. By incorporating both GWAS with validation samples as well as a gene expression study, this study takes an important first step in improving this understanding. However, there are several important limitations to this research. First, as the authors acknowledge, the sample sizes used in their study did not provide enough statistical power to reach genome-wide significance, and so the findings need repeating in larger studies. Second, the authors note that identifying so called “pure” never smokers from multiple study sites in several countries is a very difficult task. Finally, even if the finding is robust, it is currently unclear how it will directly improve the diagnosis or treatment of patients with lung cancer.

Research article   |   By Dr Sowmiya Moorthie   |   Published 26 March 2010

RNA interference (RNAi) is a naturally occurring gene silencing mechanism that prevents expression of transcribed genes via double-stranded RNA molecules. The discovery of this mechanism won a Nobel prize in 2006 (see previous news) and the therapeutic potential of this process to silence the expression of harmful disease-associated genes has been the subject of intense research through the development of small double-stranded RNA molecules called short interfering RNAs (siRNAs). However, in vivo delivery of siRNAs remains a major obstacle to progress with this form of therapy; intravenous injection and viral vector mediated delivery have had very limited success, with generally poor tissue uptake. A recent report in the journal Nature, describes the use of a nanoparticle delivery system to deliver siRNA to tumours in patients with skin cancer (reported by Nature News).

In their paper, Davis et al. describe some initial finding from a phase I clinical trial assessing this technique in fifteen patients [Davis et al. (2010) Nature doi: 10.1038/nature08956]. The delivery system consists of particles approximately 70nm in diameters made up of two synthetic polymers, a protein (human transferrin protein) which engages with receptors on the surface of cancer cells and the siRNA molecule. The particles are delivered into the patients’ bloodstream where they circulate until they come into contact with solid tumours. The transferrin protein then allows targeting of the siRNA into tumour cells that are over expressing the transferrin protein receptor. Once inside the tumour the siRNA is released from the complex and acts to reduce the expression of a particular protein – in this case RRM2.

Tumour samples from three patients were analysed to assess the effectiveness of this therapy. The nanoparticles were found to localise within tumour tissue and not in nearby tissue and their accumulation was dose-dependant. In addition, the researchers measured levels of RRM2 mRNA and protein in the tumour tissue. These were reduced post-treatment in one patient; however, they were unable to determine the magnitude of the reduction. The authors acknowledge that although this study demonstrates it is possible to achieve targeted delivery of siRNAs, many issues will still need to be resolved including, the safety of the treatment and its ultimate impact in influencing tumour growth.

A further use of nanoparticles reported recently is for diagnosis of prostate cancer (see Nature News). This new assay utilises gold nanoparticles linked together by a peptide (short protein) that can be cleaved by an enzymes linked to prostate cancer. Cleavage causes a colour change reaction, even in the presence of very small amounts of enzyme. So far the assay has been shown to be highly sensitive using purified protein, but the sensitivity with actual biological samples has yet to be demonstrated. The ability to detect very small amounts of a biomarker make this assay potentially useful in cancer therapy; early diagnosis of cancer recurrence makes effective treatment more likely, but cancer biomarkers are usually only present in very small amounts at this stage and hard to detect by standard methods.

Research article   |   By Dr Susmita Chowdhury   |   Published 25 March 2010

Problems with clotting or coagulation of the blood may dispose to hemorrhage (excessive bleeding) or thrombosis (excessive clotting), and this can lead to stroke, heart attack, pulmonary embolism, bleeding disorders and other serious conditions, giving rise to the most common causes of mortality and morbidity in the Western world. Activated partial thromboplastin time (aPTT), which may be either prolonged or shortened, is considered to be a global test of thrombolytic tendency.


Recently researchers at the University of Edinburgh [Houlihan LM et al. Am J Hum Genet. 2010 Mar 18] aimed to identify polymorphisms causing variation in a measure of the time it takes blood to clot (called activated partial thromboplastin time, aPTT) in the general older population via genome wide association methods. A total of 1477 Scottish adults from 1921 and 1931 birth cohorts were included in initial aPTT measurements, and genotypic information from 488 individuals were used for analysis.


The scientists identified associations of genome-wide significance with relatively large effect sizes between aPTT and variants in three genes, F12, KNG1 and HRG. These genes all have important functional roles in the blood coagulation cascade, which is a series of reactions that cause blood to clot by the formation of cross-linked fibrin clot. For example, the F12 gene encodes the coagulation factor XII precursor molecule, which is involved with the initiation of blood coagulation. Mutations in any of these genes could potentially lead to coagulation disorders; for example, variation in HRG has been linked to thrombophilia, in which aPTT is prolonged.


The study findings showed that the variants in the three genes accounted for approximately 18% of the variance of aPTT which, the authors proposed to be a relatively substantial proportion.


Comment: Since the participants had an average age of 79 at the time of the study and come from the same geographical region, findings from a validation study on a younger population and different area would be of interest. The findings of this study may be followed up to establish their clinical significance while further experimental studies are required to establish the mechanisms by which these genes prolong aPTT in vitro and influence thrombosis in vivo. Overall, this study makes an important contribution to knowledge about the genetics of blood clotting, especially because so few genes seem to account for such a relatively large effect.


Research article   |   By Dr Sowmiya Moorthie and Dr Philippa Brice   |   Published 23 March 2010

Lung cancer is the most common cancer in the world and the survival rate among diagnosed patients is poor. The majority of lung cancer cases are non-small cell lung cancers (NSCLC) and usually surgical removal is the first line of treatment. An important factor in improving survival of these patients is identifying those that will benefit from additional chemotherapy following this procedure, i.e. those with more aggressive tumours, in whom the prognosis for a cure based on surgery alone is poor. Selecting such individuals is based on assessing risk factors that can be measured after surgery such as tumour stage, residual tumour mass and vascular invasion among others. However, these methods are not always successful at distinguishing patients who will need additional therapy from those for whom the prognosis is good.

Molecular studies into NSCLC have suggested that it may be possible to associate tumour gene expression profiles with patient survival. As a result many researchers have tried to develop gene expression-based tests which can be used as an additional factor in determining prognosis. A recent paper published in the Journal of the National Cancer Institute evaluated studies that reported prognostic gene expression signatures in NSCLC and found that there was little evidence that any of the reported gene expression signatures were ready for clinical application [Subramanian and Simon (2009) J Natl Cancer Inst. doi:10.1093/jnci/djq025]

The review evaluated studies published between January 2002 and February 2009, and identified 16 articles that were relevant. The studies were then evaluated against a number of criteria including appropriateness of study design, statistical validations and medical utility for the new signatures beyond that obtained using existing treatment guidelines. None of the studies succeeded in showing improvements in predictive power over known risk factors. The authors conclude that studies which are investigating prognostic factors need to be designed with a focus on intended use and proposed a set of guidelines to aid their design and analysis. The guidelines cover areas such as defining objectives, data collection and reporting, statistical analysis and presentation of results and importantly demonstrating clear medical utility.

Comment: The findings do not necessarily show that gene expression profiling cannot improve prognosis for this group of lung cancer patients – merely that there is not sufficient evidence to demonstrate it. Given the financial investment in such research, it seems only sensible that more thought should be given to optimal study design and reporting. Similarly, although the technique has shown considerable promise for breast cancer prognosis, to the point where there has been significant commercial development, reliable scientific evidence of clinical benefit has been hard to come by (see previous news). Of course, the technique which has shown considerable prognostic promise for breast cancer – may not be effective for all types of tumour. However, generating reliable evidence as to the efficacy (or otherwise) of this sort of clinical tool certainly requires careful thought – in this instance, improved study design and reporting.

Research article   |   By Dr Caroline Wright   |   Published 22 March 2010

The recent harvest of common genetic susceptibility variants uncovered by genome-wide association studies has raised hopes of personalised medicine and the use of individual genetic risk prediction to prevent disease. However, a mounting number of studies have shown that an individual’s genetic risk based on common single nucleotide polymorphisms (SNPs) does not substantially improve risk prediction based on traditional (non-genetic) risk factors (see previous news cardiovascular disease and diabetes).

A new study evaluating the utility of using common genetic variants in breast cancer risk models, published in the New England Journal of Medicine, has come to much the same conclusion [Wacholder S. et al. NEJM (2010) 362:986-93]. Combining four prospective cohort studies and a case-control study allowed nearly 6,000 cases and 6,000 controls to be followed for up to 15 years. Each individual’s risk of breast cancer was retrospectively calculated based on ten SNPs and four clinical risk factors which are part of the standard Gail model (number of first degree relatives with breast cancer, age at menarche, age at first live birth and number of previous breast biopsies), all of which individually have fairly small relative risks. Numerous risk models were constructed and compared in terms of their ability to discriminate between those who developed breast cancer from those who didn’t, using the area under the ROC curve (AUC, which varies from 0.5-1.0, where a value of 1.0 indicates a perfect prediction). The purely genetic model (AUC=0.59) performed as well as the Gail model (AUC=0.58), but the combined risk model had the best performance with an AUC of 0.62. Although this represents a modest improvement in performance, the incremental benefit is unlikely to justify the increased cost of genotyping for individuals. In addition, almost half the cases ended up in the same quintile of risk irrespective of whether the model included genetic variants. The authors therefore concluded that “even with the addition of these common variants, breast-cancer risk models are not yet able to identify women at a reduced or elevated risk in a clinically useful way.”

Comment: This conclusion may be somewhat pessimistic, as highlighted in the accompanying editorial [Devilee P & Rookus M.A. NEJM (2010) 362:1043-5]. Although an AUC of around 0.6 is certainly too low for accurate clinical prediction, the authors have “implicitly dismissed” the pure Gail model for clinical risk prediction, because it performs similarly well (or as poorly) as the purely genetic model. Importantly, however, these models differ substantially in terms of their feasibility for implementation; the ‘assay’ required for the Gail model – a simple questionnaire – is substantially cheaper, easier and faster than genotyping.

Although this study adds to the mounting evidence that common genetic variants are unlikely to be useful for risk prediction at the individual level, there are still plenty of reasons for optimism. Firstly, these common genetic risk variants reveal important information about the underlying biology of complex diseases, which may ultimately lead to better treatments. Secondly, genotyping these common risk variants could still be useful at a population level for targeting preventative interventions such as screening (see previous news). And finally, future studies using deep or whole genome sequencing methods may uncover more susceptibility variants, including rare variants with a substantially higher relative risk, that may improve risk prediction. For the moment, however, there is still very little evidence that personalised risk prediction – such as that offered to consumers by a wave of new companies (see previous news) – is worth the extra cost and logistical challenge of implementing genotyping in clinical practice.

Research article   |   By Dr Philippa Brice   |   Published 14 March 2010

This week, the first findings from whole-genome sequencing of people with rare genetic diseases have been released. Hitherto performed for only a few healthy individuals, researchers have now used high-throughput genomic sequencing of DNA from two families with different inherited disorders.


Reporting in The New England Journal of Medicine, Lupski et al. present whole genome sequencing of a person with Charcot-Marie-Tooth disease (CMT), in whom a causative mutation had not previously been identified. Investigation of functional variants in a total of 40 genes known to be involved in other neurological diseases identified a number of candidate variants, which were then genotyped in other family members [Lupski JR et al. N Engl J Med. 2010, DOI: 10.1056/NEJMoa0908094]. Two mutations (one of them novel) were identified in the SH3TC2 gene; each of four affected siblings possessed both mutations, whereas the four healthy siblings and parents had no more than one of the mutations each. Investigations showed that each mutation was associated with different physiological effects.


A second paper in Science reports whole-genome sequencing of a healthy couple and their two children, each with two different genetic diseases, Miller syndrome and primary ciliary dyskinesia [Roach JC et al. Science. 2010, DOI: 10.1126/science.1186802]. Comparing the genome sequences of the parents and children made it easier to identify possible disease-associated mutations because it was possible to identify matching familial (inherited) regions and exclude these from consideration as possible mutations, effectively reducing the number of candidate disease genes from 34 to just four.


Of these, one (in the DNAH5 gene) had previously been identified as a cause of primary ciliary dyskinesia and was assumed to be causative in this case, whilst separate (earlier) exome sequencing – that is, sequencing only exons, which is quicker and cheaper than the full genome – identified a mutation in the DHODH gene as the most probable cause of Miller syndrome in the children [Ng SB et al. (2010) Nat Genet. 42(1):30-5].


Both papers conclude that the rapidly falling costs of whole-genome sequencing make it increasingly feasible that clinical geneticists will use family genome analysis to investigate families with rare inherited disorders, to obtain precise diagnoses and hopefully, improved information about the probable clinical features and course of the disease in each patient based on the underlying mutation/s.


Comment: In the excitement over the mid- to long-term prospects for generalised improvements in disease prediction and prevention that are likely to arise from affordable, rapid whole genome-sequencing, we have perhaps been inclined to overlook the potential impact on families with rare genetic diseases. It is often very difficult for clinical geneticists to precisely identify causative mutations and to give any idea of the prognosis, since many genetic diseases have very variable symptoms. These first demonstrations of how the short-term future may look for medical genetics are very promising.

Research article   |   By Dr Caroline Wright   |   Published 11 March 2010

Whilst the vast majority of human DNA is located in the nucleus, a small amount is also present in the mitochondria – the ‘power houses’ of  the cell – and mutations in one of the mitochondrial DNA (‘mtDNA’) is responsible for several serious rare inherited disorders (see previous news). Unlike the nuclear genome, however, which is usually only present as a single copy per cell, there are generally around 50-100 mitochondria per cell, and around 5-10 copies of mtDNA per mitochondrion. The rate of mutation is also much higher in mitochondrial DNA than nuclear DNA, due to the absence of proof reading and correcting enzymes. Therefore, in addition to having multiple copies of identical mtDNA in a cell (homoplasmy), cells may also have multiple alternative copies (heteroplasmy) which may also vary between different cells and tissues.

The advent of massively parallel sequencing methodologies makes it technically feasible to investigate mitochondrial genetic heterogeneity, as is allows very rare variants to be detected. A new paper in Nature reports the sequencing of mtDNA samples from both normal and cancerous human cells [He Y et al. Nature (2010) doi: 10.1038/nature08802]. In the non-cancerous cells, an average of 28 novel mtDNA homoplasmic alleles were identified in a single individual which were not present in the mtDNA reference sequence (see the MitoMap database). In addition, in areas of known variation, an average of 4 heteroplasmic alleles were identified per sample, which were either maternally inherited or arose as de novo somatic mutations early in development, and had tissue-specific allele frequencies of between 7-91%.

As expected, the cancerous cells (derived from colorectal tumours) had higher mitochondrial genetic heterogeneity, with 20 cancer-specific variants detected, most of which were heteroplasmic. Interestingly, the heteroplasmic variants detected in the normal colon tissue were either entirely absent from the cancer cells or present in homoplasmy, supporting the hypothesis that cancer cells evolve from aberrant stem cells across many cellular generations over many years. The authors suggest that these cancer-specific mtDNA mutations could prove to be excellent biomarkers to track cancer progression because, unlike genetic rearrangements that are characteristic of nuclear DNA in cancer cells (see previous news), they are 500-1,000 fold more numerous in the cells. Moreover, minor changes are easier to detect because of the relatively small size of mtDNA.

Research article   |   By Dr Philippa Brice   |   Published 4 March 2010

Remarkably, every human body contains ten times as many (much smaller) microbial cells as it does human cells. Interest in the role of this ‘microbiome’ in health and disease has been growing over recent years (see previous news), especially with the advent of faster genome sequencing. Now a new paper in Nature by an international team of researchers led by the Beijing Genomics Institute describes the human gut microbiome. Commensal gut microbes are important for normal nutrition and digestion, and provide protection from harmful microbes; it is thought that changes in the normal composition of gut microbes may be involved in a range of conditions such as bowel disease and obesity. 

Faecal samples from 124 Europeans from the European MetaHIT consortium were analysed for microbial genes; some people were healthy, others overweight, obese or with irritable bowel disease (IBD). Over 99% of the genes sequenced were bacterial in origin, leading the researchers to estimate that each individual had at least 160 different bacterial species present in their gut, with a collective total of more than 1000 species for the whole group [Quin J et al. (2010) Nature 464, 59-65].

A small number of species were present in most or all individuals (a conservative estimate identified 57 species that were present in90% or more of those tested), but the relative abundance of bacteria of some of even these most common species varied enormously, from 12 to over 2000-fold difference between individuals for a given bacterial species. The researchers next compared the microbial genes present between healthy individuals and those with ulcerative colitis and IBD. Statistical analysis showed very distinctive patterns of bacterial genetic profiles between these three groups

The researchers plan to extend this sort of analysis to more subjects from different countries via the International Human Microbiome Consortium, as well as sequencing of all the human associated bacterial genomes.

Comment: This research provides proof-of-concept that metagenomic sequencing is feasible, and could be useful for further study into how variation in gut microbes may playa role in certain diseases, although this work in itself does not provide any insight into how bacteria could affect these conditions beyond the observation of differences between modest numbers of healthy and diseased subjects. Co-author Professor Jeroen Raes commented:"It will allow us to understand diseases better…We know there is a microbial component but we don't know exactly how [it works]. We will use it for prognostic and diagnostic markers so we can predict disease severity or sensitivity to these diseases" (see BBC news).

Research article   |   By Dr Sowmiya Moorthie   |   Published 2 March 2010

An important aspect in the prevention of cardiovascular disease involves risk prediction in order to identify individuals at high risk and tailor treatment strategies. Risk prediction is usually based on knowledge of conventional risk factors (e.g. blood pressures, smoking, cholesterol levels) and family history. More recently, genome-wide association studies (GWAs) have led to the identification of many genetic markers associated with cardiovascular disease and it is hoped that inclusion of such information may help refine risk prediction models. However, risk prediction based on genetic factors is a complex process requiring knowledge based on the cumulative effects of multiple common risk variants (see previous news).

In a paper published in JAMA, Paynter et al. have conducted a literature-based selection of genetic markers associated with either cardiovascular disease or intermediate phenotypes (e.g. blood pressure, cholesterol) in order to construct two genetic risk scores [Paynter et al. (2010) JAMA 303(7):631-7]. The genetic markers were selected using the online catalogue from the NHGRI of GWA studies published between 2005 and 2009. 101 SNPs were used in the construction of the primary genetic risk score. The second score, limited to SNPs with a published association with incident cardiovascular disease, included 12 SNPs after pruning.

The predictive ability of these scores was tested using data available from the Women’s Genome Health Study (WGHS), an ongoing project to identify genetic variations in women underlying a range of serious illnesses, including heart disease, stroke, diabetes, breast cancer and osteoporosis. The study is surveying genetic differences among 28,000 initially healthy American women who have been tracked for more than a decade for the development of many common health disorders.

Information from a total of 19 313 participants was analysed after limiting for those of Caucasian background (to avoid population stratification) for whom complete data were available for both the traditional risk factors and for the genetic risk scores. In addition to assessing the predictive ability of genetic information alone, the authors also assessed the predictive ability of this information in combination with known cardiovascular disease risk factors and compared genetic information to information reported on family history.

Both genetic risk scores were associated with increased risk after adjustment for age, but when used alone neither had the ability to discriminate between those who were at increased risk and those who were not. In addition, neither genetic score remained associated with incident cardiovascular disease after adjustment for traditional risk factors whereas family history did. The authors state “Our study finds no clinical utility in a multi locus panel of SNPs for cardiovascular risk based on the best available literature”.

Comment: It has been widely suggested that findings from GWAs could be combined with population data in order to produce estimates of absolute risk for numerous common complex diseases (see previous news). This information could be used to stratify populations into risk categories in order to better target preventative interventions such as screening (see previous news).  In addition to associations between genetic factors and risk, knowledge about the mechanisms by which these factors contribute to risk is also needed both for better stratification and, more importantly, for the development of novel treatments. The recent  PHG Foundation report Predicting the risk of coronary heart disease with conventional, genetic and novel molecular biomarkers concluded that statistical considerations coupled with available empirical studies make it unlikely that the associations are strong enough to have an important general influence on the discriminatory ability of risk models at present.

New reviews and commentaries

Selected new reviews and commentaries, 2 March 2010

Reviews & commentaries : by Dr Philippa Brice

Stem cells: Big roles for small RNAs.
Slack FJ. Nature. 2010 Feb 4;463(7281):616

Time for the epigenome.
Nature. 2010 Feb 4;463(7281):587.

Valid concerns.
Nature. 2010 Jan 28;463(7280):401-2

The impact of human copy number variation on a new era of genetic testing.
Choy KW, Setlur SR, Lee C, Lau TK. BJOG. 2010 Jan 26.

Genomics firms turn to other markets.
Hayden EC. Nature. 2010 Feb 18;463(7283):859.

Bridging science and society.
Agre P, Leshner AI. Science. 2010 Feb 19;327(5968):921.

Research ethics. NIH guidelines for stem cell research and gamete donors.
Lo B et al. Science. 2010 Feb 19;327(5968):962-3.

Host genes associated with HIV/AIDS: advances in gene discovery.
An P, Winkler CA. Trends Genet. 2010 Mar;26(3):119-131.

Open chromatin and diabetes risk.
Groop L. Nat Genet. 2010 Mar;42(3):190-2.

Understanding variable expressivity in microdeletion syndromes.
Veltman JA, Brunner HG. Nat Genet. 2010 Mar;42(3):192-3.

Regenerative medicine: Cell reprogramming gets direct.
Nicholas CR, Kriegstein AR. Nature. 2010 Feb 25;463(7284):1031-2.

Potential for revealing individual-level information in genome-wide association studies.
Lumley T, Rice K. JAMA. 2010 Feb 17;303(7):659-60.

Principles and challenges of genome-wide DNA methylation analysis.
Laird PW. Nat Rev Genet. 2010 Feb 2;11(3):191-203.

Genetic susceptibility to stuttering.
Fisher SE. N Engl J Med. 2010 Feb 25;362(8):750-2.

Gene therapy activates EVI1, destabilizes chromosomes.
Dunbar CE, Larochelle A. Nat Med. 2010 Feb;16(2):163-5.

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