By John Easton

As of July 2010, nearly 600 genome-wide association studies of 150 distinct diseases and traits had been published. They revealed hundred of specific genomic locations, each with a relatively small effect. There were more than 40 genetic variants, for example, associated just with type 1 diabetes and 30 more related to Crohn’s disease.

Despite hundreds of studies, hundreds of thousands of volunteers and billions of genotyped markers, few of the genetic signposts identified “have clear functional implications,” wrote Teri Manolio of the National Human Genome Research Institute in a review article for the New England Journal of Medicine. Narrowing an implicated locus to a single variant that directly causes susceptibility to disease by disrupting the expression or function of a protein, he added, “has proved elusive to date.”

Enter children’s cancer specialist Kenan Onel, MD, PhD, with a vastly smaller sample size, about 300 - a fraction of the usual GWAS brigade - and a much narrower, tightly focused question. Are there genetic variations, he asked, in patients who were treated with radiation therapy for Hodgkin lymphoma as children and then acquire second cancers decades after treatment?

Hodgkin lymphoma is one of the most treatable cancers, with more than 90 percent of patients surviving after a combination of radiation and chemotherapy. But nearly 20 percent of patients treated as children develop a second cancer within 30 years. The younger the patients are when treated and the higher the radiation dose, the greater the risk. This late side effect is the second leading cause of death for long-term Hodgkin’s survivors.

In Onel’s GWAS search, published last week in Nature Medicine, he found two variants relevant to these secondary cancers. Only three percent of patients with both of the protective versions developed second cancers within 30 years. But those with both of the high-risk variations-a combination found in 50 percent of those of European descent-had ten times the risk: more than 30 percent of them developed second cancers.

“This means we can identify children who are most susceptible to radiation-induced cancers before treatment begins and modify their care to prevent this serious long-term complication,” said Onel. “Our options for Hodgkin’s are broad enough that we can find ways to control the initial disease without relying on radiation therapy.”

Onel and colleagues “used very wise scientific intuition and they got some place very interesting,” Stephen Channock, head of translational genomics at the National Cancer Institute told Spoonful of Medicine. “It’s a very exciting scientific finding. They did a GWAS in a very small study…but the effect they saw was very strong.”

Onel and colleagues analyzed the genomes of 178 Hodgkin’s patients who had been treated between the ages of 8 and 20 with chemotherapy and radiation therapy. Within 30 years after treatment, 96 of them had developed second cancers and 82 had not.

When they scanned each patient’s genome, focusing on 665,313 tiny genetic variations known as SNPs, they found three variations that appeared far more often in patients with second cancers. When they repeated the study using a different set of patients - 62 cases with second cancers and 71 without - two of the three markers were significant.

Those two markers were both from a small region known as 21q on chromosome 6. Both are positioned near a gene known as PRDM1. The genetic variations closely associated with increased cancer risk, and with each other, appeared to decrease activation of the PRMD1 gene. They had no detectable effect on any other genes. Cells with the protective version of both markers expressed PRDM1 after being exposed to radiation. Cells with the variants linked to subsequent cancers did not produce any PRDM1.

Previous studies have found that PRDM1 is involved in a variety of fundamental cellular processes, including proliferation, differentiation and apoptosis - which can all go awry in cancer. The gene’s activity is lost in many cancer types.

“Taken together,” the authors note, “our findings support a novel role for PRDM1 as a radiation-responsive tumor suppressor.” PRMD1 may be important for understanding the causes of second cancers in survivors of pediatric Hodgkin’s lymphoma as well as in other cancer patients treated with radiation therapy.”

This study should also “bring some optimism” back to genome-wide association studies, Onel added.

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The University of Chicago is the birthplace of nuclear energy. So like proud but concerned parents, UChicago has kept a close eye on the benefits and challenges of nuclear power over the years since the first self-sustained nuclear reaction under Stagg Field. Thus, the battle to manage the consequences of the damaged reactors at the Fukushima I Nuclear Power Plant in Japan has drawn the University’s interest, and the short-term and long-term effects of that ongoing situation were the subject of a unique panel held on campus yesterday, “Lessons from Fukushima.”

Though nuclear power was created by scientists, discussing its use requires input from political and economic spheres as well. So the panel, assembled by the University of Chicago Alumni Association, brought together nuclear technologists (Hussein Khalil, director of the nuclear energy division at Argonne National Laboratory, and Mark Peters, deputy director of Argonne), nuclear policy watchdogs (Kennette Benedict, executive director of the UChicago-based Bulletin of Atomic Scientists), and energy economics experts (Robert Topel, director of the University of Chicago Energy Initiative). With such different perspectives, it didn’t take long for the panelists to find points of debate, reflecting the tug-of-war over nuclear power that has gone on for several decades.

Nobody disputed the magnitude of the Fukushima incident, with workers at the plant still struggling to limit core meltdown in at least three of the reactors as well as re-cooling spent fuel rods at the site. As well, the panelists agreed that the incident was very relevant to nuclear power in the United States, where roughly one-fifth of electricity is provided by nuclear plants, many of which use the same model as the Fukushima reactors. But opinions differed on what those consequences would be.

Khalil pointed out that this was the first natural disaster to cause “grave damage” to a nuclear power plant in nearly 60 years of their use, and that a similar occurrence was very unlikely in the United States. But Benedict argued that “very unlikely” wasn’t good enough for “the most dangerous technology on Earth,” and that not every safety precaution possible had been taken at Fukushima. Topel agreed with the latter point - “why build generators on the ocean side in a country that coined the term ‘tsunami’?” he asked - and noted that the renewed attention to the long-term dangers of nuclear power would only make it more difficult to build new reactors.

In fact, no new nuclear reactor has come online in the United States in 32 years, Khalil said. So while Argonne continues to research new designs for nuclear plants and new strategies for containing nuclear waste, the economic (and possibly now public opinion) barriers are too large. The most likely rescue for nuclear power may come from an unlikely source: climate change.

“If other technologies turn out to be a bust, and if we really are serious about reducing our carbon footprint and carbon pricing becomes important, then there is a technology we have that can produce a lot of energy at relatively low cost compared to the alternatives,” Topel said. “Then, nuclear energy will prosper.”

By the end of the 90-minute discussion, the panelists came back to common ground on a hopeful note. If a thin silver lining could be found on a disaster that hasn’t yet been completely averted, it’s that the events at Fukushima have re-opened the international dialogue on nuclear power - its immense benefits and equally immense costs.

“One of the positive externalities of the Fukushima accident is that many more people are interested in nuclear energy, and I think that’s terrific,” Benedict said. “It’s unfortunate that it takes an accident to do it.”

Elsewhere…

The conversation about cancer is changing, from a single disease classified by the organ where it appears to multiple diseases grouped by genetic and biological similarities. As ScienceLife has written before, the Chicago Cancer Genome Project is our local contribution to this strategic shift against “the emperor of all maladies.” This week the Los Angeles Times examined that research effort and others like it, speaking with project leader Kevin White and many of the Medical Center’s cancer experts collaborating on this new vision of how to classify and battle cancer.

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In a perfect world, patients would only have one serious condition at a time that could be treated in isolation. But that’s not the case: when a doctor is considering treatment for one disease, they must take into account the other illnesses and treatments ongoing in a patient. Even relatively innocent and common drugs, such as the anticoagulants given to prevent blood clotting in people with certain heart conditions, can cause complications during medical procedures due to the risk of increased bleeding. But alongside the risks of those drugs, occasionally there’s an unexpected benefit that falls into the lap of researchers and clinicians.

Kevin Choe and Stanley Liauw set out to study this kind of drug interloper, testing whether prostate cancer patients on anticoagulants such as Coumadin or aspirin respond differently to radiation therapy. The primary aim of their study was to assess how strong anticoagulants such as warfarin or clopidogrel added to the risk of a common side effect experienced after radiation therapy. But the two also uncovered a useful secondary effect in their retrospective study of over 500 patients - a potential benefit of anticoagulants upon long-term outcomes after radiation therapy.

“This is the nature of research; sometimes, the less expected finding is the one that might have more potential interest,” said Liauw, assistant professor of radiation and cellular oncology.

More than 180,000 cases of prostate cancer are diagnosed each year, and the disease is more prevalent in elderly male populations. That same age group also is more likely to have cardiovascular problems that necessitate chronic treatment with an anticoagulant drug to prevent heart attacks and stroke. But while slowing the blood’s natural clotting ability is a good thing for heart disease patients on a normal day, it’s a profound negative during surgery. Even in radiation therapy for prostate cancer, bleeding rarely occurs due to damage to the rectal wall, which leads radiologists to use lower doses on patients taking anticoagulants.

To better define that additional risk, Choe, a fifth-year resident in the radiation oncology program, Ashesh Jani, and Liauw began a retrospective study of patients who had received radiation treatment at the University of Chicago Medical Center. The researchers looked at the records of nearly 600 patients who had already received their treatment and compared those patients who were taking warfarin or clopidogrel to those who were not. The comparison confirmed that there was indeed an increased risk of the side effect - 15.5 percent of patients on anticoagulants reported severe bleeding compared to only 3.6 percent of controls. As a result, the authors suggested that clinicians should use caution when increasing the radiation dose in patients on anticoagulants who are unable to stop treatment due to their other illnesses.

But the project didn’t end on that down note.

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The big science story of the past 24 hours has been a paper from the Journal of American Medical Association about what caused the death of King Tutankhamun, better known as King Tut, the world’s most famous mummy. Many of the news articles have understandably focused on the “smoking gun” that killed Tut - or rather, the lack of anything so exciting as a smoking gun. Through genetic analysis and computed tomography scans, the authors determined that King Tut likely died at age 19 of a rather hum-drum combination: a bone fracture that left the Egyptian monarch vulnerable to a deadly malarial infection. “This is one sick kid,” reacted Emily Teeter, assistant curator at the University of Chicago Oriental Institute in the AP article.

But that conclusion, like most in sciences of ancient civilizations, was not universally accepted. In the midst of thousands of news articles that merely echoed the authors’ diagnosis, Naturenews put together a nice survey of conflicting opinions from Egyptologists and molecular biologists. Many experts believe that a lot of people in ancient Egypt - located along the banks of the rather mosquito-friendly Nile - were probably exposed to malaria, and many likely developed partial immunity to the disease rather than dying from it. Even one of the authors (from the amazingly-named Institute for Mummies and the Iceman), sounded a bit wishy-washy on their diagnosis. ”We will never be able to prove he died from malaria,” co-author Albert Zink told Nature.

That’s okay, because the article is interesting beyond being an uncertain coroner’s report for a famous mummy. King Tut wasn’t the only subject of the article; in all, 11 mummies from museums in Luxor and Cairo were scanned and had tissue extracted for genetic analysis. The authors used that data to construct something of a mummy family tree, organizing five generations of the “18th Dynasty” royal family that ruled Egypt from roughly 1550 to 1295 BC. The results could form the basis for an HBO drama, as evidence strongly suggested that Tut’s parents were brother and sister. Potentially as a result of that incestuous relationship, the teenage King Tut had a number of significant bone abnormalities revealed by the team’s CT scans. Combined with artifacts depicting Tut as more of a sitter than a stander and the discovery of several cane-like implements in his tomb, there’s both cultural and now physical evidence that King Tut was disabled - a Richard III for ancient Egypt, though perhaps without the villainous streak.

One sensational rumor about Tut and his family that the paper does not support is the theory that the young king and his father may have had more severe genetic disorders. Many drawings and sculptures of the time depict Tut and his father, Akhenaten as oddly feminized, leading some Egyptologists to speculate whether the two had a genetic condition such as Marfan syndrome or gynecomastia (which causes men to develop breasts). Both theories were unsupported by the research, both genetically and anatomically - the latter analysis requiring the eyebrow-raising sentence, “The penis of Tutankhamun, which is no longer attached to the body, is well developed.” Instead of having a feminizing condition, the authors conclude, the aesthetic preferences of the day likely inspired artists to give their rulers a fashionable, womanly look.

The University of Chicago has its own mummy “murder” mystery, in the form of Meresamun, a 2,800-year-old Egyptian temple singer who has never been removed from her casing. It’s become a tradition here that every time the Medical Center obtains a new CT scanner, Meresamun is the ceremonial first patient to test out the equipment. And with each subsequent scan, more has been learned about what might have killed Meresamun, with a broken jaw once thought to be the result of trauma during life discovered to be, instead, the result of poor handling after death. Last June, the University turned to a police sketch artist in Maryland to recreate what Meresamun looked like in life, but the cause of her death remains a mystery.

The first patient in the UCMC's 256-slice CT scanner, the mummy Meresamun

Radiation had a bad reputation to overcome. Known for a long time for killing its discoverer and by frightening yellow-and-black warnings, the view of radiation has softened over the years as scientists and physicians corralled its powers for good. Whether used for screening or diagnosis in the form of X-rays and CT scans or therapeutically to kill tumors, radiation has become an essential tool for physicians.

But even with all these beneficial uses, radiation remains dangerous. A recent New York Times article discussed cases where patients received overdoses of radiation during medical procedures, usually due to computer programming errors undetected by the technicians. On the heels of that report, the Food & Drug Administration - which has oversight over medical devices - unveiled a new initiative to reduce unnecessary radiation exposure. Officials hope to improve patient safety by establishing tighter requirements for manufacturers of medical imaging devices, revising the accreditation process for those who use such devices, and conducting more research to find what level of radiation exposure is safe and appropriate for patients.

I asked Michael Vannier, professor of radiology at the University of Chicago Medical Center, to explain what these changes meant for the field and patients. Vannier said that he and his colleagues welcomed the attention being paid to these issues, even as radiologists and manufacturers were already seeking new ways of getting the maximal benefits from a minimum of radiation. At the Medical Center, a state-of-the-art 256-slice CT scanner acquired in 2008 provides higher quality scans than previously possible using 30 percent less radiation, Vannier said - and a computer upgrade scheduled for next week will reduce that radiation by a further 40 percent.

“What will happen, I think, is that the manufacturers will add capabilities to the instruments that make it possible to much more automatically and reliably monitor and minimize the dose,” Vannier said. The rest of our conversation is available below.

Why is the FDA initiative happening now, and why is it necessary?

Vannier: Well, you have several incidents that have attained a lot of notoriety. But what’s also happened is that CT scanning has become extremely popular. Your chances of having a CT scan in your lifetime are extremely high, because it is a very versatile and highly available technique. But it does use X-rays, and the dose you receive from a CT scan is higher than the dose received from X-ray techniques as a general rule. You don’t want to do them unnecessarily.

The second thing is that the CT scanners themselves have improved in their dose efficiency very significantly over the years. If a scan is done with an older scanner, it may very well require a higher dose than the state-of-the-art equipment, which means that getting the same exam in different places can mean different doses received. Even if you know what kind of exam you’re getting, the instrument doing it doesn’t necessarily tell you that the dose is low.

The third thing is the general facts of physics that govern how CT scanners work. If you give a minimal dose you can get an acceptable level of noise in images and the quality can be very high. But if you double the dose, you may see no improvement in image quality, so it’s deceptive in that way, and there’s a potential of overdosing or selecting the wrong dose setting. It takes special care to ensure that the dose is maintaining the standards that are held to that we call ALARA - As Low As Reasonably Applicable, which is the FDA-mandated standard.

In the past, for CT scans in general, it was very difficult to look at scans and tell what dose was used. In the latest scanners, which we use for exams here today, it actually puts a record of the dose in with the images, a printed-out diary or record, if you will. It’s possible to know with a high degree of confidence exactly what dose was received, whereas in past years it wasn’t possible, and people using older equipment may not be included in such a system.

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