A new genetic screening process has helped researchers understand the genetic causes of cancer, such as how mutations accumulated in a person’s life can cause leukemia.

The study shows that by comparing a person’s own DNA to that of their cancerous cells, researchers can find DNA mutations that may have led to abnormal cell growth, or cancer.

After sequencing a single leukemia patient’s healthy and cancerous DNA, researchers at Washington University School of Medicine in St. Louis were able to pinpoint several mutations out of hundreds that appeared likely to have contributed to his cancer’s development. He is the second patient with acute myeloid leukemia (AML) to have his entire genome and that of his cancerous tissue fully sequenced, rather than just the portions that are known to be prone to cancer-causing mutations.

“If we only look at genes with known or suspected links to cancer, we’ll miss many mutations that are potentially relevant,” co-author Richard Wilson said in statement.

The study by Mardis et al., published in The New England Journal of Medicine, identified a total of 750 mutations in the patient’s AML genome. Most of them proved irrelevant, but 64 were likely to be cancer-related. Two previously known mutations were newly linked to leukemia.

Timothy Lay, senior author of the study, explained in a statement that most patients with this type of leukemia are treated similarly, at least in the beginning. This study’s patient, for example, received various chemotherapy drugs. Defining cancer mutations could help determine which patients need aggressive treatment, such as a stem cell transplant, and which could be effectively treated with less intense therapies.

Personalized sequencing of entire cancer genomes is possible now because the accuracy and cost of genome sequencing technology has dramatically improved. This study took only a few months at one-third the cost of the first AML patient, who was sequenced only one year ago.

To date 350 cancer mutations are known, but thousands of cancer genomes will need to be screened to truly explain the genetic basis for cancer. This information could be used not just to guide physicians to the most effective treatment, but also to inform patients about their prognosis.

But do patients even want to know?

A recent study published in the Journal of Genetic Counseling suggests they do. Researchers found that 98 of 99 patients with ocular melanoma, a rare, untreatable eye cancer, said they wanted to know if their cancer had a genetic marker that gave them a 50 percent chance of dying within five years. Patients were relieved when the risk was low, but even when the risk was high they were enabled to plan financially and make the most of their time alive.

This very personalized medicine will continue to be driven by improved diagnostic testing, finding more predictive disease markers, and new therapies directed at cancer-specific mutations, James Downing wrote in a recent editorial published this month in The New England Journal of Medicine. He believes this technology will likely be used clinically long before we have a complete knowledge of cancer genes.

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It’s not enough to teach genetics, says Michael Dougherty, director of education for the American Society for Human Genetics.  It has to be taught in the right way.

“Current teaching practices may be producing a public that is unprepared to participate effectively as medical consumers in a world where personalized medicine will rely increasingly on genetic testing, risk assessment, predispositions, and ranges of treatment options that include biological and behavioral components,” writes Dougherty in an opinion piece published online today in the American Journal of Human Genetics.

Dougherty calls for curriculum reform at all levels, from middle school all the way up through undergraduate education. The key, he says, is for students to understand that the genetics of most human traits and conditions are complex and, with only rare exceptions, not deterministic.

Dougherty suggests a new genetics curriculum that begins with lessons on traits that show continuous variation, such as height and weight, and focuses on how multiple inherited and environmental factors can affect these traits.  Teachers could then move on to discussions of genes and the molecular details of how they are passed from generation to generation.  Only here, in the later stages of their genetics education, would students learn about the rare single gene diseases, such as cystic fibrosis and PKU, that make up the bulk of today’s genetics lessons.

“Our incompleteness of understanding and the messiness of complex-trait examples are poor arguments for maintaining the status quo in our genetics classrooms.  We know on theoretical grounds that the entirety of phenotype is defined by genes and environment, and substantial uncertainty still characterizes both.  To pretend such uncertainty does not exist is to deprive students of an appreciation of both modern genetics and the nature of science.”

Dougherty points to the Genes, Environment and Human Behavior module, funded by the Department of Energy and available from BSCS, as an example of the kind of lesson that could help correct the misconceptions that students already have.  The National Human Genome Research Institute also has available a Human Genetic Variation curriculum supplement.  And of course, you can always check out the Genetics 101 section of the 23andMe website for a basic introduction to genetics.

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Researchers are sometimes frustrated when a prospective drug proves effective in some patients, but not enough to justify giving it to everyone who has the condition it is intended to treat.

The beta-blocker drug bucindolol met that fate in 2001 when it was originally tested as a treatment for heart failure. Though it did help a fraction of the 2,708 patients in the study, it didn’t improve the condition of enough patients to be approved for the market.

But now researchers have rescued bucindolol from the pharmaceutical dustbin by identifying a genetic variation that increases a person’s chances of benefiting from the drug. Researchers collected DNA samples from 1,040 patients who were involved in the original study, and found that genetics plays a significant role in determining its effectiveness. In light of the discovery, the company that owns the drug, ARCA biopharma, has applied to the FDA for approval to sell it.

The most important gene in determining bucindolol’s effectiveness is ADRB1, which is not surprising — the gene is involved in activating the “fight or flight” response to the hormone adrenaline. Beta-blocker drugs such as bucindolol suppress that response, protecting a weak heart from the strain that an adrenaline response produces.

It appears that bucindolol blocks adrenaline’s effects only if a person has a particular form of the ADRB1 gene. Among those people, bucindolol decreased the risk of death from heart-related causes 48%.

23andMe customers can determine whether they have the form of ADRB1 that responds to bucindolol by checking their genotypes at the SNP rs1801253; the CC genotype is the responsive form of the gene. 23andMe customers and demo account holders can also read more about bucindolol in the Beta-blocker Response section of My Health and Traits.

Until now, the vast majority of drugs prescribed on the basis of genetics have been for cancer — and their effectiveness has mostly depended on the genetics of the tumor rather than the patient. But the bucindolol story illustrates the broader promise of genetic information for drug developers, physicians and patients. The hope is that eventually, understanding how genetic variations influence the effectiveness of drugs and their side effects will usher in a new era of personalized medicine.

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The journal points to the incredible pace of recent discoveries associating specific genetic markers to various diseases and conditions. It even adds a few new revelations to the mix, including:

• a study that found certain variations of the stress-related gene FKBP5 increase the chances that a person who is abused as a child will later develop post-traumatic stress disorder.
• the first evidence of a causal link between the gene PON1, the antioxidant activity of a substance known as paraoxanase and a person’s chances of having a severe heart attack.
• a paper demonstrating that variations in the gene LRP5, which has previously been linked to osteoporosis, can affect bone density and risk of fracture.

More provocative is a commentary by National Human Genome Research Institute director Francis Collins and two colleagues that envisions a not-too-distant future (the year 2020) when doctors and patients will be able to tailor their health care to individualized genetic information.

The question is, how do we get from here to there? Even allowing for the incredible amount of progress that is being made, it will take an enormous amount of research to incorporate genetic information into medical practice – and even more to demonstrate that doing so is beneficial.

23andMe wants to be involved in that research effort. Though some (including the author of another commentary in the JAMA special issue) have argued it is too early to offer personal genetic information directly to the public, we believe our company can contribute to realizing the “2020 vision” advanced by Francis Collins and his co-authors.

In giving our customers access to their genetic information, 23andMe is helping to organize a group of motivated, educated people around the goal of achieving truly personalized medicine. And once we have enough customers we plan to enlist their help in research studies designed to find more associations between genes, disease and drug response – and to learn how people might benefit from having knowledge about their genomes.

It’s true that there isn’t enough evidence yet to justify taking medical action on the basis of genetic information, and we make that clear to our customers that they shouldn’t make health-related decisions based on what early research results might indicate. But if anything, that’s an argument for the existence of companies like 23andMe – by educating our customers and the general public about the potential value of genetic information, we can enlist their help in achieving the common vision of personalized medicine.

Image courtesy of U.S. Department of Energy Genome Programs (http://genomics.energy.gov)

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