Whole-exome sequencing rises to top in largest clinical application for undiagnosed disease

Posted on 02 Oct 2013 by Liz Devitt

Numerous studies have demonstrated the promise of whole-exome sequencing, which focuses on the protein-coding regions of DNA, but the clinical use of this technology has remained limited. Now, the largest report of results from this technology in a population of patients with undiagnosed disease of suspected hereditary origin highlights that the value of this testing is considerable, and that it can even uncover recessive mutations not previously linked to a given disease.

There are an increasing number of genetic tests for various illnesses, and doctors faced with a difficult-to-diagnose patient will order tests that look for mutations in a predetermined set of genes or larger chromosomal abnormalities, such as that detected by karyotype analysis. But the diagnostic success rate of such assays disappoints: karyotype analysis is only about 5% to 15%, and other methods generally fall below 20%.

A pilot study published today in the New England Journal of Medicine offers hope. It suggests that whole-exome sequencing might have as high as a 25% success rate in solving these hereditary disease mysteries. “For years we’ve known that whole-exome sequencing can identify new disease-causing mutations,” says Yaping Yang, a clinical geneticist at the Baylor College of Medicine in Houston and a study coauthor. “But this puts it on the map as a tool for clinical medicine.”

The researchers offered whole-exome sequencing, which cost about $7,000, as part of the medical care given to 250 people with undiagnosed diseases—many of whom were pediatric patients—who were referred by physicians after other methods, microarray analysis or tests looking at a single gene, failed to pinpoint the source of their illness. Whole-exome sequencing resulted in a genetic diagnosis for 62 of the patients, 20 of whom had autosomal recessive diseases—a less common finding because both parents must pass along a faulty copy of the given gene for clinical symptoms to arise. In some cases, patients had recessive mutations that hadn’t previously been reported as associated with their disease. For example, the researchers found one patient with two mutated copies of the spastic ataxia of Charlevoix-Saguenay gene, or ‘SACS’ gene, which included a new DNA deletion not previously known to cause this progressive movement disorder.

Continue reading →

Voting commences on research prize determined by public poll

Posted on 23 Sep 2013 by Elie Dolgin

It’s an off year in the US election cycle, which means that neither the President nor most members of Congress will face the voters come November. But that doesn’t mean you can’t still cast a ballot this fall. Today, the Brigham and Women’s Hospital (BWH) in Boston announced the finalists for the second annual BRIght Futures Prize, a $100,000 research contest in which the winner is decided by a public poll. Voting is now open through 21 November.

The BWH launched the prize last year in an effort to engage the public-at-large. First, the hospital’s Biomedical Research Institute (BRI) solicited grant proposals from BWH staff on various overarching themes: last year, those were personalized medicine and systems immunology; this year, the topics span the nine featured at the hospital’s ‘research day‘ in November (where the BRIght Futures Prize winner will be announced). Then, the BRI convened peer-review panels to winnow the applicants down to three finalists, each of whom made a short video to pitch their ideas to the public. (See my coverage of last year’s prize: ‘Biomedical grant awarded by ‘American Idol’-style public vote’.)

Last year’s winner was Robert Green, a clinical geneticist at BWH who proposed to sequence the genomes of 480 newborns, half from healthy babies and half from sick babies, in an effort to study how to use that information in routine medical care. Off the back of his BRIght Futures Prize, which served as a sort of pilot grant, earlier this month Green won a $6 million grant from the US National Human Genome Research Institute to roll out his plan in full. (See ‘Scientists to sequence genomes of hundreds of newborns’ from the Nature News blog.)

This year’s finalists include: Utkan Demirci*, a biomedical engineer who aims to advance a point-of-care microfluidic device for detecting levels blood levels of antiepileptic drugs; pharmacoepidemiologist Daniel Solomon and healthcare researcher Joel Weissman, who hope to create an online patient portal to streamline clinical trial enrollment and boost participation; and plastic surgeon Bohdan Pomahač and bioengineer Jeffrey Karp, who propose to develop a new generation of adhesive medical tapes based on biologically-inspired designs. (See my February 2013 news feature about Karp’s investigations of ‘biomimetic’ adhesives: ‘The sticking point’.)

You can watch all the finalists’ videos and read short descriptions of their research proposals here. Check them out, and then exercise your voting right!

*Update: Demirci was named the winner at the BWH Research Day on 21 November.

Discovery of gene variant lends muscle to understanding of statins’ side-effects

Posted on 28 Aug 2013 by Liz Devitt

Statin

The global market for statins has reached heart-stopping proportions, registering at almost $20 billion in 2012. In the US, one out of every four adults over the age of 45 is on statins, making these medications one of the leading types prescribed. The drugs work by lowering the liver’s production of low-density lipoproteins, also known as ‘bad’ cholesterol, which form the artery-clogging plaques that can lead to heart attack. But statins can cause significant side effects, ranging from sleeplessness to an increased risk of type 2 diabetes and potential liver damage.

One of the most common side effects is muscle pain and injury, which afflicts up to 38% of people taking statins. Now, researchers have hit upon a new gene variation that could explain why some individuals are less prone to this type of adverse reaction to such drugs.

The scientists themselves sound surprised at the discovery. “We weren’t focused on finding the cause of the muscle damage,” says Ronald Krauss, director of atherosclerosis research at Children’s Hospital Oakland Research Institute in California and lead author of the new study, which appears online today in Nature. “We were looking at cell lines from patients on statins to discover new gene variants and we found one that affects how the drug works.”

It’s not the first effort to look at statin side effect risks though the lens of genetics. Five years ago, researchers found that individuals on high doses of simvastatin—a statin marketed as Zocor by New Jersey-based Merck—who also carried a specific variant in the SLCO1B1 gene were fifteen times more likely to have muscle pain and injury, also known as myopathy. Based on these findings, which also correlated with markedly higher blood levels of a muscle damage biomarker, the US Food and Drug Administration set new guidelines recommending alternative medications for patients who need more than 40 milligram a day of simvastatin to lower their cholesterol.

Continue reading →

A victory for genes

Posted on 24 Jun 2013 by Nature Medicine Editor

A version of this editorial appears in the forthcoming July issue of Nature Medicine.

The ability to patent human genes has been costly to researchers and patients, and has restricted competition in the biotech marketplace. The recent US Supreme Court decision making isolated human genes unpatentable will bring freedom of choice to the patient, and level the playing field for research and development.

***

On 13 June, in a landmark decision, the US Supreme Court ruled that human genes cannot be patented. The unani- mous decision by the Court concludes a lawsuit against the molecular diagnostics company Myriad Genetics that was seeking to invalidate certain claims in three of the company’s US patents on the BRCA1 and BRCA2 genes, which were originally granted in the 1990s. This welcome ruling marks the first time that the US Supreme Court has invalidated a human gene patent.

The decision has been a long time in coming—so long that Myriad’s patents were due to expire in less than three years. And the 15-year delay has surely not aided patients who frequently benefit from healthy competition in the biotech sector or from research on BRCA genes. Yet the decision brings relief to those of us who reject the idea that an individual or corporation can own—even for a limited time—human genes and thereby control their use.

In 1994, Mark Skolnick, a future founder of Myriad Genetics, along with several other research groups, cloned BRCA1, followed swiftly by BRCA2. Myriad Genetics was founded that same year, and the company filed patents for the two genes in 1994 and 1995. Mutations in the genes are associated with increased susceptibility to breast and ovarian cancers, and Myriad has successfully translated this infor- mation into genetic testing kits. Moreover, by claiming intellectual property rights on these genes, they have precluded other companies and university-based diagnostic labs from commercializing compet- ing tests, effectively establishing a monopoly on BRCA testing.

But in 2009, the American Civil Liberties Union and the Public Patent Foundation filed a lawsuit against Myriad Genetics, the US Patent and Trademark Office and others, stating that patenting BRCA1 and BRCA2 was unconstitutional. After several rounds in lower courts, with alternating decisions in favor of and against the motion, the Supreme Court agreed in November 2012 to hear the case (Association for Molecular Pathology et al. v. Myriad Genetics, Inc., et al.).

In siding with the plaintiffs in this case, the Court’s decision rests on the interpretation of a section of the US Code governing patent law that has remained virtually unchanged since 1793. According to the Code, “any new or useful process, machine, manufacture or composition of matter, or any new and useful improvement thereof ” can be patented. Although not explicitly stated, the wording has been interpreted to mean that naturally occurring phenomena are not new or invented and therefore are not inherently patentable. In writing the Court’s opinion, Justice Clarence Thomas stated, “Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes. The location and order of the nucleotides existed in nature before Myriad found them. Nor did Myriad create or alter the genetic structure of DNA . . . . We . . . hold that genes and the informa- tion they encode are not patent eligible . . . simply because they have been isolated from the surrounding genetic material.”

Continue reading →

74 new susceptibility genes found for breast, ovarian and prostate cancer

Posted on 27 Mar 2013 by Yevgeniy Grigoryev

In the largest cancer genotyping study to date, an international team of scientists spanning more than 160 research groups has identified 74 new genetic regions associated with breast, ovarian or prostate cancer—a near doubling of the number of susceptibility loci linked to these three hormone-related cancers.

“These findings are very significant and show the power of international collaborative research that provided additional knowledge regarding the common risk factors,” says Jan Korbel, a molecular biologist who studies prostate cancer at the European Molecular Biology Laboratory in Heidelberg, Germany, who was not part of the study.

The researchers discovered the genetic regions using a custom-built genotyping array comprised of around 200,000 single nucleotide polymorphisms (SNPs) drawn mainly from previous genome-wide association studies of different cancer types. This method pinpointed 23 previously unidentified susceptibility loci linked to prostate cancer, 16 of which were associated with more aggressive and life-threatening forms of the disease. The same approach flagged 49 new SNPs for breast cancer and 11 new regions associated with ovarian cancer.

The work—the product of the EU-funded Collaborative Oncological Gene-Environment Study—was published online today in a series of 13 papers in Nature Genetics, Nature Communications, PLOS Genetics, the American Journal of Human Genetics and Human Molecular Genetics.

Similar to previous reports, these studies uncovered genetic variations in regions that are shared among the three cancers, suggesting a common genetic basis and mechanism of pathology. “We presume that these particular genes are important across cancer types, but the way these genes are regulated is different across tissues,” said Douglas Easton, director of the Center for Cancer Genetic Epidemiology at the University of Cambridge, UK, who led the breast cancer work, at a press briefing.

Many of the newly identified SNPs are located in genome regions that affect cell growth and proliferation. The authors hope the work will open the door to the future development of biomarkers and therapeutic targets for improved clinical diagnostics and intervention.

“As we understand the biology of genetic susceptibility, it may impinge directly on the way we think about the tumor biology and the personalized treatment of the tumor based on the molecular characteristics,” said University of Cambridge oncologist Paul Pharoah, a senior author of the paper on ovarian cancer, at the press briefing.

Image: Shutterstock

Patients should learn about secondary genetic risk factors, say recommendations

Posted on 21 Mar 2013 by Nature Medicine Editor

Cross-posted from the Nature News Blog

Imagine getting a chest X-ray to identify the cause of a serious cough. The radiologist finds a shadow that wasn’t causing the cough but could be a tumor. In many cases, it is obvious what to do upon uncovering these sorts of secondary or incidental findings — most doctors would follow up on the search for a possible lung tumor, for example.

But genomic information presents a special case: genes are predictive, but not perfectly so, making some results murky. And many genetic diseases and predispositions to disease don’t have clear and obvious paths for clinical management, potentially making them a lifelong psychological burden.

Today, the American College of Medical Genetics and Genomics (ACMG) released recommendations for how genome-sequencing laboratories should report incidental findings after a doctor orders a full or partial genome sequence. It defines a minimum list of about 60 genes and 30 conditions that should be reported to the doctor as part of a patient’s care, whether the patient wants to know them or not. But the guidelines stop far short of recommending that all risk factors be passed on to doctors and patients.

Click here to continue reading.

From tumors to tapeworms: parasite’s genome points to new uses for cancer drugs

Posted on 13 Mar 2013 by Yevgeniy Grigoryev

On the map: Taenia solium {credit}Shutterstock{/credit}

Commonly used cancer drugs could be repurposed to help eliminate tapeworm infections, according to the first full genome analysis of the human gut pathogen.

A team led by Matthew Berriman, a geneticist who studies parasites at the Welcome Trust Sanger Institute in Hinxton, UK, sequenced the genomes of three human-infective tapeworm species as well as a fourth tapeworm that lives in the intestines of rats and mice. Their analysis, published online today of Nature found that among more than 1,000 gene products that are predicted to be druggable in the parasite responsible for echinococcosis—a disease that affects an estimated 2–3 million people worldwide—more than 200 already have existing therapies (many in the oncology space) that block them.

“By providing reference genomes for these tapeworms, the study lays the foundation for the identification of new potential drug targets to kill the worms,” says P’ng Loke, a microbiologist at the New York University Langone Medical Center who was not involved in the study.

The cancer link makes sense given the life cycle of the tapeworm, notes Berriman. People typically ingest the parasite as eggs or larvae that then migrate to the host’s intestines where they develop into adult tapeworms. “When larvae infiltrate tissues and organs and cause large proliferating growth, [it’s] like metastasizing cancer,” he says.

The potential for new pharmacological interventions doesn’t end there, though. The genome map also revealed that the tapeworm’s parasitic lifestyle has led to a number of gene losses and molecular simplifications that could provide a wormy Achilles’ heel. Thanks to evolution, for example, tapeworms have lost genes involved in oxidative stress response, making them reliant on just one enzyme for this kind of cell detoxification.

Fortunately, drug repurposing could prove successful here, too. The tapeworm enzyme involved in oxidative stress, called thioredoxin glutathione reductase, is the target of multiple drugs that have been shown to kill blood flukes and flatworms. “We have identified clear vulnerabilities in the pathways the parasites rely on,” Berriman says.

Competition intensifies over market for DNA-based prenatal tests

Posted on 27 Feb 2013 by Kevin Jiang

Prenatal DNA testing has been a fiercely contested market of late. Yet another competitor entered the fray last week when Natera, a startup based in San Carlos, California, announced the 1 March launch date of a commercial test that can detect chromosomal abnormalities in the developing fetus from just a drop of an expectant mother’s blood—and with a sensitivity on par of that of more invasive techniques such as amniocentesis and chorionic villus sampling, both of which carry an elevated risk of miscarriage.

Natera now joins three other California-based firms—Sequenom, Verinata Health (a division of sequencing giant Illumina) and Ariosa Diagnostics—in offering such products for women at high risk of having babies with Down’s syndrome or other chromosomal miscounts known as aneuploidies. With US health insurers, including Aetna and Wellpoint, saying they plan to cover the new tests, the market for DNA-based prenatal screening now provides “a billion dollar opportunity,” according to David Ferreiro, an analyst at Oppenheimer & Co. in Boston.

Between the four new tests, Verinata’s and Sequenom’s currently offer the widest range of screening options, with the ability to identify disorders associated with an extra X or Y sex chromosome, such as Klinefelter’s (XXY) and triple X syndrome. This flexibility is reflected in the cost: Sequenom’s MaterniT21 PLUS carries a list price of $2,762, almost twice as much as Natera’s Panorama, which can detect a missing X chromosome but not other kinds of sex chromosome irregularities.

The tests’ sensitivities vary depending on the chromosome, but all companies claim to be able to identify a fetus with Down’s syndrome, caused by three copies of chromosome 21, more than 99 times out of 100. Detecting extra copies of chromosome 13—a condition known as Patau’s syndrome—is more difficult, and Ariosa’s Harmony test does poorest here, with only 80% sensitivity. But it’s also the cheapest, with a sticker price of just $795 (see chart for the full comparison).

Noninvasive Prenatal Genetic Tests Compared{credit}Nature Medicine{/credit}

For now, the DNA-based tests are only thought to provide a screening tool for select populations, and are not considered definitively diagnostic by clinician groups such as the National Society of Genetic Counselors, who worry about the possibility of erroneous results, the lack of data in low-risk populations and the limited number of aneuploidies tested. Thus, most experts—and many of the companies themselves—still recommend that women whose DNA-based tests come back positive follow up with conventional tests such as amniocentesis. Although the additional testing will still mean invasive procedures for some pregnant women, and their attendant complications, “you are limiting those invasive tests to only the high risk groups,” says Joan Scott, a genetic counselor and executive director of the National Coalition for Health Professional Education in Genetics in Lutherville, Maryland.

Ultimately, “women and their providers [need to be] well informed about the benefits and limitations that are inherent in all these tests,” says Scott. “It’s not a cut and dried decision.”

A version of this story appears in the April 2013 issue of Nature Medicine.

Mutations that drive early-onset prostate cancer identified, pointing way to specific treatments

Posted on 11 Feb 2013 by Yevgeniy Grigoryev

Prostate cancer affects an estimated one in every six males who live past the age of 70, making it the most common type of cancer among men worldwide. The majority of prostate cancer cases occur in men 65 years of age or older, but about 2% of cases occur in those under the age of 50—and these early tumors are particularly aggressive. Until now, scientists didn’t know whether the mechanisms that give rise to prostate cancer in the younger men were different from those in seniors.

New findings, published today in Cancer Cell, show that in young patients prostate cancer develops through a distinct mechanism driven by androgen hormones, such as testosterone. “This brings up the intriguing possibility to develop future screening tests for prostate cancer geared towards young men in which testosterone levels are particularly high,” says molecular biologist Jan Korbel of the European Molecular Biology Laboratory in Heidelberg, Germany.

In an effort to understand the genetic and biological basis of prostate cancer in young men, Korbel and his colleagues sequenced the entire genomes of tumor cells isolated from 11 early-onset prostate cancer patients and compared them to the genomes of tumor cells obtained from seven elderly-onset prostate cancer patients.

The study revealed that the androgen receptors that bind testosterone were much more active in the tumor samples from the younger individuals than the older ones. Further analysis linked this testosterone-driven activation to increased DNA rearrangements that cause cancer, and additional data from more than 10,000 patients confirmed this connection. What’s more, the researchers observed that in the cells from nine out of 11 early-onset patients, testosterone activated androgen receptors that triggered the gene TMPRSS2 to ultimately fuse the gene ERG, promoting cancer. In contrast, the genomic landscape of elderly patients revealed abnormalities that were not linked to the androgen receptors’ activity.

Levi Garraway, a medical oncologist at Harvard’s Dana-Farber Cancer Institute in Boston who was not involved in the current study, thinks that the new link between the genomic landscape of prostate cancer and androgen-driven biology is “encouraging because half of the drugs [approved by the US Food and Drug Administration] for prostate cancer are attacking the androgen axis.” This reinforces that early-onset prostate cancer patients should receive such androgen-targeting drugs as part of first-line treatment. It’s “more bang for the buck,” Garraway says.

“[The] next step in the field should be to first stratify treatments for early and late onset,” Korbel says. Further studies are needed to asses if such tailored screening can lead to greater success in the disease detection, but the observed DNA rearrangement mechanisms in early-onset patients can be a more general phenomena as studies have shown that such rearrangements also lead to chromosomal alternations in breast, ovarian and pancreatic cancers.

Image: Shutterstock

Gene sequencing yields breakthrough for children with rare Parkinson’s-like disorder

Posted on 30 Jan 2013 by Yevgeniy Grigoryev

Doctors can now use a person’s genetic sequence as the basis for rational drug selection—a sign of how far personalized genomics has come in recent years. A case report published today in the New England Journal of Medicine illustrates the strength of this approach.

The paper describes an extended Saudi Arabian family in which many young siblings suffered from a Parkinson’s-like condition affecting their movement. The children had normal levels of neurotransmitters dopamine and serotonin in their spinal fluid, suggesting they should have been healthy. The unique circumstances prompted researchers to use the latest advances in genomic sequencing to identify a mutation in the SLC18A2 gene, which encodes the protein vesicular monoamine transporter 2, or VMAT2, as the cause of the disease.

A team led by Berge Minassian, a neurologist at the Hospital for Sick Children in Toronto, successfully pinpointed the mutation and treated the symptoms in these siblings. “I am certain that in the next few years patients walking into children’s hospitals will have their whole genomes sequenced,” says Minassian. Until now, magnetic resonance imaging (MRI) has been the primary diagnostic tool for people with neurological diseases.

The study’s initial patient was a 16-year-old girl first diagnosed with muscle weakness when she was just four months old. She sat for the first time when she was two and a half years old, began crawling at four and walking—and only with difficulty—at the very late age of 13. Her symptoms resembled Parkinson’s disease, but all her metabolic and MRI tests came back normal. Doctors also ran tests on her 2-year-old sister who suffered from similar symptoms and a red flag showed up in the toddler’s urine, where dopamine levels were below average. The physicians then gave the 16-year-old and her three younger siblings levodopa-carbidopa, a dopamine precursor used to treat Parkinson’s. They were puzzled, though, when the conditions worsened in all four.