News

28 May 2009The long standing gene patents held by Myriad Genetics, for diagnosing a predisposition to breast and ovarian cancer using BRCA1 and BRCA2  testing, are now facing a legal challenge that could threaten the validity of all gene patents (reported in Science).

 

In the US District Court of New York, on 12th May 2009, a lawsuit was filed against not only Myriad Genetics but also the US Patent and Trademark Office and the University of Utah Research Foundation. The challenge is lead by the American Civil Liberties Union (ACLU) and the Public Patent Foundation on behalf of breast cancer and women's health groups, individual women, and scientific associations representing around 150,000 researchers, pathologists and laboratory professionals (see ACLU press release).

 

Numerous mutations in both BRCA1 and BRCA2 genes predispose women to a high risk of getting breast and ovarian cancer. Women with a family history of these diseases often use genetic testing to help decide on a plan of treatment or prevention, including increased surveillance or preventive mastectomies or ovary removal. The patents granted to Myriad give the company exclusive rights to perform diagnostic tests on the BRCA1 and BRCA2 genes and to prevent any clinician or US-based researcher from looking at the genes without first getting permission from Myriad. According to the lawsuit, “such monopolistic claims over these genes hampers clinical diagnosis and serves as a disincentive for research”. Additionally, the patents “block women's access to medical information necessary for making vital health care decisions”, as the high price tag may prevent women from being tested or seeking a second opinion.

 

Comment: Although the scope of the BRCA1 patent has been altered on several occasions (see previous news), both the BRCA2 and amended BRCA1 patents have ultimately been upheld in Europe by the European Patent Office (see previous news). However, even the existing patents are significantly more prohibitive in the US than across Europe, because there is no exemption for research under US patent law.

 

If this new American challenge is successful, the validity of these and many other gene patents may change across the globe. Far from being limited to these specific patents, the current lawsuit challenges the whole notion of gene patenting, claiming that gene patents are illegal under patent law because genes are "products of nature", which can only be identified not invented. The premise upon which gene patenting is based relates not to the genetic sequence, but to its isolation and purification, a notion that dates back to the early 1900’s when a patent on adrenalin purified from glands was granted. However, although around 20% of all human genes have been patented, the validity of applying this principle to genes has been widely questioned.

 

The US Secretary’s Advisory Committee on Genetics, Health and Society recently released a draft report for public consultation on gene patents and their impact on patient access to genetic tests, to which the PHG Foundation responded. The draft report was launched prior to the filing of this lawsuit, and falls substantially shy of recommending against gene patenting. Nonetheless, it highlights the increasingly pertinent issue of how the thousands of existing gene patents will affect complete genome sequencing, and vice versa. The outcome of this trial is therefore likely to have far-reaching consequences, not only for clinical genetics, but also for the development and use of commercial full genome sequencing services.

27 May 2009

Measurement of blood prostate specific antigen (PSA) is currently the most widespread screening method for prostate cancer. However, the benefits of PSA screening still remain unclear despite the publication of two large-scale prostate cancer screening trials (see previous news), as the benefits of testing may be outweighed by the harms of potential misdiagnosis and unnecessary intervention.

Recent linkage and genome-wide association studies have helped to elucidate the genetic basis of this common complex disease, with numerous genetic variants identified as being associated with the condition, fuelling the hope that genetic testing may provide better risk-prediction for prostate cancer. Despite modest risk estimates from individual SNPs, Zheng and colleagues have previously suggested that combining five SNPs with family history may be useful for predicting prostate cancer (Zheng et al. (2008) NEJM 358(9):910 and see previous news). But how does this genetic test for prostate cancer perform and does it have any clinical utility?

Recent work by Li-Wan-Po and colleagues [Li-Wan-Po et al. (2009) Public Health Genomics DOI:10.1159/00218710] attempts to answer this question. Using the cumulative association of five genetic risk factors (SNPs) with family history, Li-Wan-Po et al. calculate the positive and negative predictive values in order to determine how good a predictor this test would be. Despite the positive predictive value increasing with the number of factors included, the test performs poorly even when five or more factors were included, with only 44% of positive tests accurately predicting prostate cancer. They also highlight that although the odds ratios increase as the number of SNPs included increases, the test performance actually decreases because the prevalence of the combined genotypes is low. The highest risk class – with nearly 4.5-fold higher risk of developing prostate cancer relative to the population average – represents less than 1% of the population, making it inappropriate for screening.

Zheng et al. have also previously shown that genotypes at the five genetic variants do not correlate with disease state, Gleason score, or PSA level at diagnosis, suggesting that this genetic test cannot identify those men at a higher risk of a more clinically aggressive disease outcome. When combined with the fact that the genetic test does not even predict prostate cancer as well a single PSA test between the age of 44 and 50 (which is not currently recommended by the UK National Screening Committee), the performance of the genetic test is clearly woefully inadequate for either clinical or public health purposes. Furthermore, combining PSA testing with the genetic test only leads to a marginal, though statistically significant, improvement in test performance [Sun et al. (2008) Prostate 68: 1257-1262].

Comment: Li-Wan-Po et al. are correct in pointing out that “the benefit of screening for prostate cancer is still uncertain with PSA measurement” and “that the proposed 5-genetic-variant test for risk estimation of prostate cancer is inadequate”. Even with the addition of further genetic variants to the PSA test, only a small improvement in test performance is gained. Analyses currently suggest that adding these SNPs to existing measured clinical factors (such as age, Gleason score and serum PSA level) provides no additional benefit in identifying men that are at a higher risk of a more clinically aggressive form of prostate cancer. The technical performance of this test is inadequate and does not help to address any of the harm issues currently muddying the waters with PSA screening. Although results are promising, and susceptibility tests for prostate cancer based on these genetic variants are already available direct-to-consumer, there is still a long way to go before the test can be considered “ready for prime-time”. This study provides a useful case-example of the some of the issues that need to be considered in the development of genetic screening tests and their suitability for wider clinical use.

26 May 2009The European Parliament has signalled a more systematic approach towards rare diseases in a debate held on 23rd April 2009, when a substantial majority of MEP’s adopted a report from the Committee on the Environment, Public Health and Food Safety (Rapporteur: Antonios Trakatellis). Rare diseases individually affect less than 5 per 10,000 individuals, but together affect between 27 and 36 million European citizens (6-8% of the population) during their lives.

 

The report contends that adopting a strategic approach to rare diseases was deemed to be an ‘absolute necessity’. At European Commission level, the recommendations include the provision of sustainable funding and support for Orphanet, a European database that provides information about research, the availability of medicines and treatment and location of specialist centres (Amendment 31). They also include the submission of an implementation report by the end of 2012 to include the budgetary measures necessary for effective implementation of the Community Programme on Rare Diseases, the creation of relevant centres of expertise, the collection of epidemiological data and the mobility of experts, professionals and patients (Amendment 34).

 

Recommendations to member states include identifying national centres of excellence and compiling a catalogue of experts at national level by 2011, and adopting a comprehensive strategy aimed at guiding and structuring all relevant actions on the field of rare diseases by 2010 (Amendment 11). Member states are also encouraged to fund appropriate treatments to ensure equitable access to high quality care to allow the primary prevention of these diseases (Amendment 14) and where appropriate, to allow patients to travel between member states to receive treatment (Amendment 18). Significantly, member states are urged to ‘encourage efforts to avoid rare diseases which are hereditary, and which will lead finally to the eradication of those rare diseases, through:

(a)   genetic counselling of carrier parents; and

(b)   where appropriate and not contrary to existing national laws and always on a voluntary basis, through pre-implantation selection of healthy embryos’ .

(Amendment 15)

 

This recommendation in particular has received a mixed response. The Secretary of the International Federation of Fertility Societies, Dr Richard Kennedy welcomed the ‘mature approach of European authorities’ and suggested that the use of PGD offered ‘a very real way of giving parents the opportunity to remove the risks of serious diseases’ allowing children to be spared the ‘fear that what is written in their genes might condemn them to a serious illness in later life’ (reported in Medical News Today).

 

The view of the UK Human Genetics Commission was more circumspect: an open letter dated 21 April to MEPs from the Chair of the Commission Professor Jonathan Montgomery suggested that ‘if this recommendation were construed as promoting directiveness in genetic counselling it would represent a significant departure from established practice and accepted clinical ethics’. He went on to argue that genetic counselling ‘should not be used as an opportunity to encourage people to chose a particular reproductive option: to do so would threaten the professional integrity of counsellors and undermine the non-directive ethos of genetic counselling’. Although the wording of Amendment 15 stresses the need for voluntary adoption of PGD, the references in the Traketellis report suggests that MEPs have adopted a somewhat simplistic approach to the enormous problems involved in eradicating such diseases.

21 May 2009The UK National Institute for Health and Clinical Excellence (NICE) has launched a new portal to allow both health and social care professionals to access sources of clinical and non-clinicalevidence. NHS Evidence will “help users identify the best evidence by sorting, sifting and prioritising a range of information”. Chief operating officer Dr Gillian Leng commented: “This is just the first stage in the development of an impartial service which will provide the most comprehensive source of relevant and trustworthy information about clinical, non clinical evidence and best practice, at the touch of a button. It’s good news that users, including patients, will be able to find the information they need and know that it comes from a credible source” (see press release).  Of note, PHG Foundation publications are readily accessible via this new portal. 

Bodies that produce official forms of guidance that meet specific criteria (producing systematically developed statements such as clinical and referral guidelines) may also apply for additional formal accreditation from an independent advisory body. There is to be regular review of new publications to allow the timely identification of relevant new evidence in different contexts, and systems for highlighting on the web, via newsletters and RSS feeds [Leng GC (2009) Lancet 373(9674): 1502-4].

On the website, it is possible to search within specific interest areas: clinical, commissioning, drugsand technologies, education and learning tools, public health and social care. The portal also allows users to search specialist collections and databases, books and journals; searches are ranked by relevance and quality. There will be ongoing development of NHS Evidence, which also has the capacity to commission the development of evidence-based information from external agencies and to engage with users and stakeholders to support the use of evidence in decision-making.

19 May 2009Tay Sachs disease (TSD) is an autosomal recessive genetic disease caused by mutations in the hexosaminidase A (HEXA) gene; it results in progressive neurological degeneration. The most common form of TSD is lethal in infancy or early childhood, and there is no effective treatment. However, biochemical or molecular (DNA) testing is possible and can be used to identify unaffected carriers at risk of passing the disease on to their children.

Although TSD is a very rare disease, with the carrier frequency in the UK general population only around 1 in 250-300, this figure is substantially increased in Jewish populations of Ashkenazi origin (those originating from Central or Eastern Europe). Here, the carrier frequency around ten times higher at around 1 in 25-30, due largely to three specific mutations. Carrier screening for TSD in the Ashkenazi Jewish population is therefore feasible, and screening programmes have proved highly effective in reducing the prevalence of TSD. Carrier testing been funded by the National Health Service (NHS) since 1999 in the UK. If two carriers wish to have children together then advice from clinical geneticists would be recommended, since there is 25% chance that their children will have TSD.

In a project commissioned by the UK Newborn Screening Programme Centre (part of the National Screening Centre), the PHG Foundation worked with Guy’s and St Thomas’ Clinical Genetics Service in London and an expert Advisory Group to undertake a needs assessment and review of current TSD screening services in the UK. The final report from this project, Tay Sachs Disease carrier screening in the Ashkenazi Jewish population, is now available, and sets out the findings and recommendations from this work.

The UK Jewish population is relatively small at around 270,000, many living in areas of London and Manchester. The report authors found that carrier screening currently takes place in different contexts:  outreach community screening is provided on a voluntary basis by Jewish charities in selected schools, universities and community centres. Testing for carrier status in may also be accessed via clinical genetics services, two walk-in clinics in London, and from the antenatal setting, with the actual testing being performed at NHS laboratories in London (Guy’s) and Manchester (Willink). However, there is a lack of systematic screening provision. A survey of antenatal screening in 114 hospital trusts showed that screening was not routinely offered, even in areas with large Jewish populations, and there was confusion as to which women ought to be offered testing.

In fact, patient surveys revealed a good level of awareness of Ashkenazi Jewish ethnic origins; 97% of respondents had four Jewish grandparents, but they had mostly heard about screening from family or friends or via the internet, rather than as part of their antenatal care or from a health professional. One third of patients undergoing testing who were interviewed were already pregnant. The report concludes with a set of recommendations that could be used to strengthen the NHS carrier testing offered to the UK Ashkenazi Jewish population, which could also be relevant to screening provision in other countries.

Referring to the report, Dr Ian Ellis, Consultant Clinical Geneticist at the Alder Hey Children's Hospital in Liverpool and member of the expert Advisory Group for the project commented: “People have to realise that Tay-Sachs has not gone away, but only through constant vigilance and screening can families be made aware of the potential risk and their options. This report documents the previously haphazard arrangements for Tay Sachs screening in Britain. The report is comprehensively written and provides an opportunity for building Tay-Sachs screening into current NHS screening plans”.

Dr Anne Mackie, Programme Director for the UK National Screening Committee, stated: "The UK NSC believes that antenatal Tay Sachs testing should be available for individuals from high risk populations - including the Ashkenazi Jewish population - who seek it.  We are asking NHS commissioners to assess the need for this service in their area and provide a service to those who have a reason to seek it". See also NSC policy position on Tay Sachs disease screening in pregnancy; this refers only to antenatal and not community screening.

19 May 2009Personal genomics, or ‘recreational’ genomics as it has been dubbed, is proceeding a pace. Consumer genomics companies 23andMe, deCODE Genetics and Navigenics have grabbed numerous headlines and inspired seemingly countless commentaries over the last year. Offering genome-wide scans direct-to-consumer (DTC) via the internet that purport to tell individuals their risk of developing various diseases – for the relatively affordable price of $399-$2500 – these companies sequence less than 0.05% of the genome, focussing primarily on common single nucleotide polymorphisms (SNPs).

 

The relative new-comer Knome (pronounced “Know-Me”) is the only DTC company to date offering full-genome sequencing. Costing around $100,000, this service was initially available only to the very rich. However, Knome has now expanded their offerings to a wider audience. Following the auctioning of a single full-genome sequencing service on eBay for $68,000 (see Knome press release), Knome is now offering complete exomic sequencing for $24,500 (see Business Wire). By concentrating only on the coding regions of the genome, this service involves sequencing around 1-2% of the entire genome, focussing only on those parts known to code for functional products, and works out at just under $1 per gene.

 

Aimed particularly at couples and families (for whom the services is discounted to $19,500 per person), George Church, founder of Knome, states that the service will “allow us to track gene-specific inheritance patterns across generations, identify shared traits and explore common ancestry. In certain cases, a comparative analysis between healthy and affected individuals within a family can potentially lead to the identification of implicated genes, which could help further advance scientific understanding of a specific condition.”

 

Comment: Complete exomic sequencing has already been used to aid clinical research (see previous news), but this is the first time it will be available DTC. By offering targeted sequencing of all genes, rather than genome-wide scanning for common polymorphisms, the service raises a very different set of issues for several reasons. Firstly, the vast majority of gene-disease associations found to date for multifactorial diseases have been located within non-coding regions of the genome, and presumably relate to control of gene expression rather than sequence changes in the resulting protein(s). Therefore, unlike the other major consumer genomics companies, this service is unlikely to offer much information regarding genetic susceptibility to common complex diseases. Secondly, because the vast majority of rare inherited disorders are caused by changes to the gene sequence, complete exomic sequencing has the potential to deliver some very nasty surprises to the unwary consumer. However, regardless of the potential benefits and risks, there is little doubt that as genome sequencing technologies continue to develop and become cheaper, both complete and partial genome sequencing will become widely available over the next 5-10 years.

15 May 2009 The Public Health Agency of Canada has announced that scientists from Canada's National Microbiology Laboratory have completed the full genome sequence of samples of the H1N1 influenza virus, which is associated with the recent human swine flu outbreak. Canadian Health Minister Leona Aglukkaq commented: "This is the first complete sequencing of the H1N1 flu virus and it's vitally important to our understanding of this outbreak” (see Yahoo news report). Importantly, no significant differences were identified between the genomes of viral isolates from different parts of Mexico and Canada, suggesting that the apparently greater severity of many Mexican cases compared with those in the rest of the world may be due to factors other than viral virulence (see press release). Determining the sequence of viruses from affected individuals in different parts of the world is critical for understanding how the viral strain functions and causes disease, how it may vary over time and in different locations, and for developing an effective vaccine.

Simultaneously, scientists from the UK Health Protection Agency (HPA) have sequenced the genome sequence of the H1N1 virus from an infected British individual. HPA Director Professor Maria Zambon said: "The pure sample of virus that we have isolated, together with its genetic fingerprint, will be important resources as scientific organisations join forces on the development of an effective vaccine” (see press release). Of note, this viral genome sequence is also highly similar to that from other isolates; expert Professor Wendy Barclay of Imperial College London explained “That’s good news because if we manage to produce a vaccine against one chosen strain the chances are that we will have cross-protection against all the strains” (see Times news report). It is likely to be several months before a vaccine will be available.

Meanwhile the World Health Organization (WHO) is said to be investigating a claim that the H1N1 virus may have been inadvertently created in a laboratory growing influenza viruses in eggs for research or vaccine production (as opposed to the direct transfer of a swine virus to non-porcine host organisms including humans), based on the genetic sequence (see Bloomberg news article). However, Nancy Cox of the US Centers for Disease Control and Prevention influenza division said that they had found no evidence that the H1N1 virus strain was derived from growth in eggs, but remained interested in determining its origin.

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14 May 2009 Newborn screening involves the testing of blood samples from newborn babies for various different rare genetic disorders. In some cases, early identification can allow interventions to prevent or ameliorate disease; other potential benefits of early, pre-symptomatic diagnosis include avoiding the need for medical investigations and allowing prompt genetic counselling of families (for example, with reference to the risk of recurrence in future children).

In the US, a wide panel of disorders are included in newborn screening programmes, 29 conditions are deemed mandatory and another 25 secondary conditions have been recommended for inclusion in screening (see previous news). Expanded newborn screening has raised some concerns and a white paper published by the President’s Council of Bioethics discusses some of the ethical implications of newborn screening in the US (see previous news). More recently, the Citizen’s Council on Health Care (CCHC) has also released a report outlining concerns about expanded newborn screening (reported by Medical News Today). Both these reports have expressed concern about provision of informed consent, as with the inclusion of much rarer conditions, it becomes much harder to ensure that people are aware about the test, the consequences of the results (i.e. false positives and negatives) and are appropriately advised about them. Many would contend that allowing parents to refuse testing which is in the best interests of the newborn child is in itself unethical, but for conditions where the clinical benefits of early diagnosis for the affected child are debatable, this argument is perhaps less compelling.

In addition to the issue of informed consent to screening, the CCHC report also expresses reservations about the retention of blood spot specimens and their use in research. Screening newborn involves collection of a small specimen of blood onto filter paper, referred to as dried blood spots, which are subsequently analysed in the laboratory. Left-over specimens are usually stored and used in follow-up testing, monitoring of the screening programme and public health research. In the UK, dried blood spot specimens are usually stored for a period of up to five years and the use of blood spots for research is governed by a Code of Practice, ensuring confidentiality. The debate on whether blood spot specimens can be retained or destroyed after screening, has led the American College of Medical Genetics (ACMG) to release a position statement (see press release). In their statement, the ACMG reaffirm the value of residual blood spots for improving newborn screening and child health. They state that specimens are stored “with rigorous control and respect for privacy and confidentiality to protect the public”. In addition they also recommend that in states that decide not to retain blood spots after screening, individuals should be given the option of depositing their children’s dried blood spots in a national repository.

13 May 2009In the US, the National Institutes of Health (NIH) recently issued for public comment draft guidance on the federal funding of research on human embryonic stem cells, intended to implement President Obama’s recent Executive Order 13505 lifting a previous ban on such funding (see previous news). The new guidelines permit "funding for research using human embryonic stem cells that were derived from embryos created by in vitro fertilization for reproductive purposes and were no longer needed for that purpose”.

In other countries with restrictive regulations on stem cell research, the US developments have further increased pressure from scientists to ease restrictions. South Korea recently reversed a ban on stem cell research using human oocytes (eggs), granting approval to a new research project using oocytes from aborted human fetuses. The ban was originally imposed in 2006 following a scandal surrounding Professor Hwang Woo-suk, a prominent South Korean stem cell researcher who in 2004 published a paper reporting the creation of the first cloned human embryo (see previous news). However, this research not only generated ethical controversy leading to his resignation from Seoul National University (see previous news) but was also subsequently discredited (see previous news) and the paper retracted by Science.

Now a research team from Seoul's Cha General Hospital have received approval from the national presidential committee on bioethics for a new therapeutic cloning project, subject to specific conditions. The researchers will be required to minimise the use of oocytes as far as possible by the use of laboratory animal experiments, to obtain formal written consent from oocyte donors for the researchers, and to establish an internal oversight body to guard against potential ethical abuses. The committee also stipulated that the research project title must not use phrases that could raise unrealistic expectations, such as a previous reference to ‘stem cell research which can cure diseases such as Parkinson's’ (see Yahoo news report). An unnamed health official reportedly commented “"We have never technically banned stem cell research but we have always called for strict guidelines" (see Reuters news report). A similar research application to use human cells from Hwang, who is currently working on animal cloning, was rejected by the committee; he remains on trial for various charges relating to the discredited human cloning research, as well as embezzlement.

Meanwhile, the Japanese Council for Science and Technology Policy is expected to approve amendments to current regulations governing stem cell research, removing the requirement for approval from a ministerial commission such that approval would only be needed from a local institutional review board. Therapeutic human cloning (the creation of human embryos for research into or treatment of serious human disease, as opposed to reproductive cloning) is expected to be permitted from this month for basic research purposes (see Nature news).

7 May 2009At the end of 2008, the European Court of Human Rights (ECHR) ruled that the permanent retention of cellular material and DNA profiles from innocent individuals in the National DNA database is in violation of Article 8 of the European Convention on Human Rights (see previous news). The ECHR described the practice of keeping permanent records of suspects in the DNA database for England and Wales as “blanket and indiscriminate”, as they do not distinguish between convicted criminals and innocent people. This contrasts with the database for Scotland, which was deemed “fair and proportionate”, where profiles are destroyed if a person is neither charged nor convicted, and are only retained for up to five years in the case of adults charged with violent or sexual offences.

 

Nearly five months on, and the UK Government has launched its proposals on how to comply with this ruling (see BBC news). These include: retaining indefinitely all DNA profiles of anyone convicted of an offence; destroying all cellular samples once a digital DNA fingerprint has been taken; retaining the profiles of unconvicted suspects for six years, or 12 years in the special case of those arrested for violent or sexual crimes; and removing the DNA profile for children when they turn 18.

 

Unsurprisingly the proposals have met with fierce opposition from all sides. Whilst some fear that the new proposals will significantly affect the ability of the police to fight crime, stating that a DNA database is of no threat to law abiding citizens (see commentary in The Guardian), others believe that the Government has not gone far enough, citing potential future misuse and abuse of the data and arguing that retention of DNA profiles from innocent people for up to 12 years is unjustified and infringes personal privacy (see Liberty).

 

Comment: According to the Home Office, the UK’s DNA database is the largest of any country, containing profiles of over 5% of the population. However, whilst no one doubts the importance of DNA evidence in forensics, the number of crimes that have been entirely solved as a direct result of this database is unclear. The question is therefore one of proportionality – achieving a fair and proportionate balance of protecting the rights of citizens, who are assumed to be innocent until proven guilty, against the needs of the criminal justice system.

 

In its 2007 report, The forensic use of bioinformation: ethical issues, the Nuffield Council on Bioethics recommended that “the law in England, Wales and Northern Ireland should be brought into line with that in Scotland… the retention of profiles and samples can be justified as proportionate only for those who have been convicted. In all other cases, samples should be destroyed and the resulting profiles deleted from the National DNA Database.” It is unclear why the Government has chosen to ignore this suggestion.

25 May 2009

Down's Syndrome (DS) or trisomy 21, the most common form of aneuploidy to affect liveborn children, is a condition associated with the presence of a whole or partial additional (third) copy of chromosome 21. The condition is the most common genetic cause of learning disability, affecting around one in every 700 births. The characteristic clinical features of DS are presumed to arise from the abnormal dosage of certain genes present on the additional copy of chromosome 21. Similarly, abnormally high expression of chromosome 21 genes is thought to be involved in the altered risk of developing specific diseases associated with DS – for example, an increased risk of early onset Alzheimer’s type dementia and of leukaemia, and a substantially decreased risk of many other forms of cancer.

A new paper in Nature presents a possible mechanism for this decreased risk of solid tumours in individuals with DS [Baek KH et al. (2009) Nature May 20, doi:10.1038/nature08062]. A team led by researchers from the Vascular Biology Program at the Children’s Hospital Boston in the US investigated the idea that the suppression of angiogenesis (the formation of new blood vessels) could be involved. The growth of new blood vessels is an important stage in the formation of solid tumours; individuals with DS have also been noted to have a reduced incidence of other diseases related to angiogenesis such as atherosclerosis. Additionally, the Down's syndrome candidate region-1 (DSCR1) gene on chromosome 21 encodes a molecule that suppresses vascular endothelial growth factor (VEGF)-mediated signalling involved in angiogenesis, via the calcineurin pathway.

The authors report a 1.8-fold increased level of DSCR1 expression in tissues from DS fetuses compared with control fetuses of the same gestational age. Analysis of a mouse model of DS revealed a 1.7-fold increase in expression levels of the corresponding DSCR1 protein compared with that in normal mice. They then examined the growth of two forms of tumour in DS mice (induced by transplantation), and observed significantly suppressed tumour growth and fewer small blood vessels (microvessels) associated with the tumours compared with normal mice. Microvessel density was also compared for tumours created from samples of induced pluripotent stem (iPS) cells derived from normal and Down’s Syndrome human cells and transplanted into immunodeficient mice; as expected, microvessel density was lower in the DS-derived than the normal tumours.

The authors propose that other chromosome 21 genes might well inhibit tumour formation via similar mechanisms, and report evidence to support an additional inhibition of angiogenesis and tumour growth mediated by the mouse Dyrk1a gene, which has previously been implicated in other phenotypic features of DS. Lead researcher Dr Sandra Ryeom said:"I think there may be four or five genes on chromosome 21 that are necessary for angiogenesis suppression…In huge databases of cancer patients with solid tumors, there are very few with Down syndrome. This suggests that protection from chromosome 21 genes is pretty complete" (see press release). However, the paper notes that individuals with DS also “have less exposure to environmental and other factors that contribute to tumour incidence”.

Comment: This paper contributes a plausible explanation of the genetic basis and pathway by which another of the observed features of Down’s Syndrome may arise. This not only contributes towards the expanding understanding of this condition, but also identifies the DSCR1 molecule as a potential target for drugs to help prevent or to treat selected cancers in individuals with DS, and potentially also in the general population – another example of how the study of genetic and chromosomal forms of disease can provide insights potentially relevant to much wider patient populations.

11 May 2009Recent years have seen rapid advances in the development of technologies that allow massively parallel high-throughput sequencing, referred to as next generation sequencing (NGS) platforms. These platforms have been applied to a number of sequencing studies including examination of RNA-sequencing, whole genome sequencing (see previous news) and genome-wide association studies. The ability of these new sequencing technologies to rapidly generate vast amounts of sequence data at a lower cost makes them suitable for population studies such as the 1000 genomes project (see previous news) and population targeted sequencing studies that look at particular candidate genes and their association with disease.  However, sequencing platforms differ considerably in a number of areas including the sequencing chemistry utilised, their technical capabilities such as read length and the methods used for data analysis.

In order to better understand issues that may be faced in data generation and analysis using different sequencing platforms, researchers at the Scripps Research Institute and the Craig J. Ventor Institute evaluated three NGS platforms for targeted sequencing (reported by Genome Web). In their study, the researchers compared the ability of Roche 454, Illumina GA and ABI SOLiD platforms to carry out targeted sequencing of the same 260kb sequence from four individuals [Harismendy et al (2009) Genome Biol. 10(3)R32]. In addition, they compared the data generated by NGS platforms with that generated by traditional Sanger sequencing using an ABI Sanger platform. The authors found that the NGS platforms were able to accurately detect known single nucleotide polymorphism (SNP) variants and had a false negative rate comparable to ABI Sanger. However, the data generated by each of the platforms varied, which was attributed to biases in sample library preparation, variation in sequence coverage depth and systematic errors with each of the platforms. Due to these differences, data from different platforms cannot be used in the same study. The authors recommend optimisation of the uniformity of per-base sequence coverage and reduction of the systematic errors that affect variant calling accuracy in order to effectively balance cost and data quality for population targeted sequencing studies.

Comment: Technological advances have led to the rapid development of a wide array of sequencing platforms. An understanding of the technical aspects of each platform is required in order to identify the best approach for research as well as medical diagnostics applications. Although the platforms used in the above study have been updated since this research was carried out, the paper does allow some insight into the issues that may be encountered when using different sequencing platforms.

6 May 2009 Mental retardation is defined as a disability that leads to severe limitations in both intellectual and adaptive abilities, including social, conceptual and practical skills with onset before 18 years. X-linked mental retardation (XLMR) refers to inherited conditions which are caused by defects in the X-chromosome, the effects of which are seen more severely in males than females. The underlying genetic cause may either be due to mutations in individual genes or large scale deletions, insertions or aneuploidies affecting multiple genes. Approximated 80 genes located on the X-chromosome have been linked with XLMR, the most well known of which is the FRM1 gene involved in fragile X syndrome. However, in many cases of XLMR the causative mutations on the X-chromosome are unknown and it has been postulated that rare mutations in many genes contribute to the condition.

A paper published in Nature Genetics describes a sequencing based approach in order to identify rare variants that lead to XLMR. In their study, Tarpey et al targeted approximately 720 genes on the X-chromosome for resequencing and systematic screening [Tarpey et al (2009) Nat Genet. 41(5):535-43]. DNA from 208 individuals from families with XLMR, as well as control DNA from individuals without mental retardation, was sequenced and screened for variants. Nine genes associated with XLMR were identified and abnormal genes responsible for XMLR in 25% of the families were identified, including three new candidate genes. However, although this strategy led to the identification of some XLMR related genes, a large number of sequence variants were also discovered that were benign; mutations leading to loss of function of some protein coding genes were found in both normal as well as XLMR individuals, suggesting they are compatible with normal existence.   

The inability to detect the genetic cause of disease in 75% of the families was attributed to the difficulties in associating many of the identified variants with disease and also to the possibility that mutations in non-coding regions or in micro-RNA sequences could also contribute to XMLR. In addition, large-scale copy number variations and inversions, which were not examined in this study, may also contribute to the condition.

Comment: Although this targeted resequencing approach was able to identify three new candidate genes, the study also illustrates the difficulties faced in identifying rare variants that cause disease. This is mainly because of the difficulty in differentiating between benign and pathogenic variants, especially when the same phenotype (in this case XLMR) may be a result of many different rare variants. Although sequencing technologies are progressing fast, both this paper and previous resequencing ventures – such as the Ventor and Watson genomes (see previous news) and the identification of an inherited cancer gene (see previous news) – illustrate the large amount of sequence variation present in individual genomes, and highlight the enormous analytical and clinical challenge ahead of finding and validating truly disease causing mutations.

 

1 May 2009Genetic Risk Prediction - Are We There Yet?
Kraft P, Hunter DJ. N Engl J Med. 2009 Apr 23;360(17):1701-3

Common genetic variation and human traits
Goldstein DB. N Engl J Med. 2009 Apr 23;360(17):1696-8

Genomewide association studies - illuminating biologic pathways
Hirschhorn JN. N Engl J Med. 2009 Apr 23;360(17):1699-701

Genomewide association studies and human disease
Hardy J, Singleton A. N Engl J Med. 2009 Apr 23;360(17):1759-68

Screening for MCAD deficiency in newborns
Loughrey C, Bennett MJ. BMJ. 2009 Mar 12;338:b971

The trouble with screening
Lancet. 2009 Apr 11;373(9671):1223

Newborn blood collections. Science gold mine, ethical minefield
Couzin-Frankel J Science. 2009 Apr 10;324(5924):166-8

Stem cells: Fast and furious
Baker M. Nature. 2009 Apr 23;458(7241):962-5

Genetics of type 1A diabetes
Concannon P, Rich SS, Nepom GT. N Engl J Med. 2009 Apr 16;360(16):1646-54

Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies
Harley IT, Kaufman KM, Langefeld CD, Harley JB, Kelly JA. Nat Rev Genet. 2009 May;10(5):285-90

Linking DNA methylation and histone modification: patterns and paradigms
Cedar H, Bergman Y. Nat Rev Genet. 2009 May;10(5):295-304

Validating, augmenting and refining genome-wide association signals
Ioannidis JP, Thomas G, Daly MJ. Nat Rev Genet. 2009 May;10(5):318-29

Data sharing in genomics - re-shaping scientific practice
Kaye J, Heeney C, Hawkins N, de Vries J, Boddington P. Nat Rev Genet. 2009 May;10(5):331-5

Non-genetic heterogeneity - a mutation-independent driving force for the somatic evolution of tumours
Brock A, Chang H, Huang S. Nat Rev Genet. 2009 May;10(5):336-42

The genetics of bipolar disorder
Barnett JH, Smoller JW. Neuroscience. 2009 Apr 7. [Epub ahead of print]

Patent pools: an idea whose time has come
Sukkar E BMJ. 2009 Apr 21;338:b1630. doi: 10.1136/bmj.b1630

Genome scans: impatient for the payoff
Koenig R. Science. 2009 Apr 24;324(5926):448

Developmental biology: Two by two.
Cyranoski D. Nature. 2009 Apr 16;458(7240):826-9

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