A new study has found that one in three early-stage breast cancer patients who received genomic testing when deciding about treatment options felt they did not fully understand their discussions with physicians about their test results and their risk of recurrence. About one in four experienced distress when receiving their test results.

Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the findings suggest there is room for improvement in communicating cancer recurrence risks and treatment decisions with patients.

Genomic testing is an increasingly important part of care for patients after they are diagnosed with early stage breast cancer. The test, which looks at 21 genes in breast tumors removed during surgery, can indicate the chance the patient’s cancer will recur. Such information can help guide decisions by physicians and patients about chemotherapy treatments. Patients with a high risk of recurrence may opt for more aggressive treatment, while those with lower risk may safely avoid over-treatment and its potential side effects. It can be challenging, however, for physicians to determine the best way to talk to patients about their test results and to use the results to make important treatment decisions with patients. Currently, there is little consensus regarding the most effective method to communicate risk information to patients.

Noel Brewer, PhD, assistant professor of health behavior and health education at University of North Carolina’s Gillings School of Global Public Health, and Janice Tzeng, MPH, who worked on this study as a graduate student at the school, led a team that examined how women with breast cancer received and understood cancer recurrence risk information after receiving a genomic diagnostic test called Oncotype DX, that is gaining widespread acceptance by oncologists and insurers.

To find out more about women’s reactions, investigators mailed surveys to 77 women with early-stage, estrogen receptor-positive breast cancer who received Oncotype DX between 2004 and 2009. The study was funded by a five-year grant from the American Cancer Society.

“Almost all women agreed that having the test gave them a better understanding of their treatment options’ chances of success,” said Brewer. “Most women said that they would have the test if they had to decide again today, and that they would recommend the test to other women in their same situation,” he added. Also, most women accurately recalled their genomic-based recurrence risk results, he said. These findings suggest that patients have a positive attitude about genomic testing, and testing helps them better understand their treatment options.

While many women understood discussions about their genomic test results, a third reported not fully understanding these discussions. Although 87 percent of women received a low or intermediate breast cancer recurrence risk score, about a quarter of the women experienced distress when receiving their test results. The authors concluded that their findings suggest a need to improve risk communication and treatment decision making after patients undergo genomic testing.

A Henry Ford Hospital study has shown a link between Vitamin D levels and basal cell carcinoma, a finding that could lead researchers to better understand the development of the most common form of skin cancer.

In a small study, researchers at Henry Ford and Wayne State University found elevated levels of Vitamin D enzymes and proteins in cancerous tissue taken from 10 patients compared to normal skin tissue taken from them.

Previous studies have linked Vitamin D deficiency with certain cancers but this is believed to be the first time researchers looked at Vitamin D and basal cell carcinoma.

“This finding may help us in future research to determine whether vitamin D plays a causative or reactive role in the development and progression of skin cancer,” says Iltefat Hamzavi, M.D., senior staff physician in Henry Ford’s Department of Dermatology and the study’s lead author.

The study will be presented at the Photomedicine Society’s annual meeting in Miami, one day before the American Academy of Dermatology’s annual meeting.

Basal cell carcinoma, which affects about 1 million Americans a year, is the most common form of skin cancer. This cancer forms in the basal cells of the deepest layer of the skin. Mohs micrographic surgery is one of the most effective treatments for removing skin cancer.

The 10 patients enrolled in the study were diagnosed with basal cell carcinoma and ranged in age from 43 to 83. All had biopsies taken of cancerous tissue and surrounding normal skin tissue. Researchers found a 10-fold increase in Vitamin D enzyme levels and a two-fold increase in Vitamin D protein levels. The enzymes and proteins help regulate levels of Vitamin D in the skin. Two genes that play a role in DNA and tumor repair also had elevated levels of Vitamin D in cancerous tissue compared to normal tissue.

A research project in the Academy of Finland’s Research Programme on Nutrition, Food and Health (ELVIRA) has brought new knowledge on the hereditary nature of gluten intolerance and identified genes that carry a higher risk of developing the condition. Research has shown that the genes in question are closely linked with the human immune system and the occurrence of inflammations, rather than being connected with the actual breakdown of gluten in the digestive tract.

“Some of the genes we have identified are linked with human immune defence against viruses. This may indicate that virus infections may be connected in some way with the onset of gluten intolerance,” says Academy Research Fellow Päivi Saavalainen, who has conducted research into the hereditary risk factors for gluten intolerance.

Saavalainen explains that the genes that predispose people to gluten intolerance are very widespread in the population and, as a result, they are only a minor part of the explanation for the way in which gluten intolerance is inherited. However, the knowledge of the genes behind gluten intolerance is valuable in itself, as it helps researchers explore the reasons behind gluten intolerance, which in turn builds potential for developing new treatments and preventive methods. This is essential, because the condition is often relatively symptom-free, yet it can have serious complications unless treated.

Researchers have localised the risk genes by using data on patients and on entire families. The material in the Finnish study is part of a very extensive study of thousands of people with gluten intolerance and control groups in nine different populations. The research will be published in a coming issue of Nature Genetics.

Research into hereditary conditions has made great progress over the past few years. Gene researchers now face their next challenge, as a closer analysis is now needed of the risk factors in the genes that predispose people to gluten intolerance. It is important to discover how they impact on gene function and what part they play in the onset of gluten intolerance.

Gluten intolerance is an autoimmune reaction in the small intestine. Roughly one in a hundred Finns suffer from this condition. The gluten that occurs naturally in grains such as wheat, barley and rye causes damage to the intestinal villi, problems with nutrient absorption and potentially other problems too. Gluten intolerance is an inherited predisposition, and nearly all sufferers carry the genes that play a key part in the onset of the condition. The only known effective treatment is a lifelong gluten-free diet.

The thousands of bacteria, fungi and other microbes that live in our gut are essential contributors to our good health. They break down toxins, manufacture some vitamins and essential amino acids, and form a barrier against invaders. A study published in Nature shows that, at 3.3 million, microbial genes in our gut outnumber previous estimates for the whole of the human body. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, working within the European project MetaHIT and in collaboration with colleagues at the Beijing Genomics Institute at Shenzhen, China, established a reference gene set for the human gut microbiome a catalogue of the microbe genes present in the human gut. Their work proves that high-throughput techniques can be used to sequence environmental samples, and brings us closer to an understanding of how to maintain the microbial balance that keeps us healthy.

“Knowing which combination of genes is necessary for the right balance of microbes to thrive within our gut may allow us to use stool samples, which are non-invasive, as a measure of health,” says Peer Bork, whose group at EMBL took part in the analysis. “One day, we may even be able to treat certain health problems simply by eating a yoghurt with the right bacteria in it.”

This catalogue of the microbial genes harboured by the human gut will also be useful as a reference for future studies aiming to investigate the connections between bacterial genetic make-up and particular diseases or aspects of people’s lifestyles, such as diet.

To gain a comprehensive picture of the microbial genes present in the human gut, Bork and colleagues turned to the emerging field of metagenomics, in which researchers take samples from the environment they wish to study and sequence all the genetic material contained therein. They were the first to employ a high-throughput method called Illumina sequencing to metagenomics, dispelling previous doubts over the feasibility of using this method for such studies.

From a bacterium’s point of view, the human gut is not the best place to set up home, with low pH and little oxygen or light. Thus, bacteria have had to evolve means of surviving in this challenging environment, which this study now begins to unveil. The scientists identified the genes that each individual bacterium needs to survive in the human gut, as well as those that have to be present for the community to thrive, but not necessarily in all individuals, since if one species produces a necessary compound, others may not have to. This could explain another of the scientists’ findings, namely that the gut microbiomes of individual humans are more similar than previously thought: there appears to be a common set of genes which are present in different humans, probably because they ensure that crucial functions are carried out. In the future, the scientists would like to investigate whether the same or different species of bacteria contribute those genes in different humans.

The jumping gene or “Sleeping Beauty” transposon is “Molecule of the Year 2009″. This was announced by Professor Isidro T. Savillo, President of the International Society for Molecular and Cell Biology and Biotechnology Protocols and Researches (ISMCBBPR). The transposon was generated by Dr. Zsuzsanna Izsvák, Dr. Zoltán Ivics and Dr. Lajos Mátés of the Max Delbrück Center for Molecular Medicine in Berlin-Buch. According to the jury, it was selected out of 15 molecules nominated in the contest because “this molecule holds great promise for gene therapy”. The jury pointed out that it can stably transfer genes even to stem or progenitor cells and is safer than a viral vector. It is the first time that the Molecule of the Year has been awarded to major recipients outside the USA in Europe.

Transposable elements are molecular parasites that propagate themselves in genomes. But at the same time they provide plasticity to the genome that clearly contributed to the evolution of gene function across the tree of life. About half of the human genome is derived from ancient transposable element sequences.

However, due to mutations, the vast majority of the transposons became inactivated. Based on transposons in fish that are presumed to have been active approximately 20 million years ago, Dr. Ivics and Dr. Izsvák resurrected a jumping gene more than ten years ago. They named the transposon Sleeping Beauty, because they literally awakened it after a long evolutionary “sleep”.

The scientists modified the originally reconstructed transposon so that it acquired a highly elevated potency in gene transfer. In its award citation, the jury noted that this hyperactive transposon promises to be a revolutionary technology platform for genetic engineering in vertebrates.

Most skin cancers are highly curable, but require surgery that can be painful and scarring.

A new study by Loyola University Health System researchers could lead to alternative treatments that would shrink skin cancer tumors with drugs. The drugs would work by turning on a gene that prevents skin cells from becoming cancerous, said senior author Mitchell Denning, Ph.D.

The study was published Jan. 15, 2010 in the Journal of Biological Chemistry.

More than 1 million people in the United States are diagnosed with skin cancer each year. In the new study, researchers examined a type of skin cancer, called squamous cell carcinoma, that accounts for between 200,000 and 300,000 new cases per year.

Squamous cell carcinoma begins in the upper part of the epidermis, the top layer of the skin. Most cases develop on areas that receive lots of sun, such as the face, ear, neck, lips and backs of hands. There are various surgical treatments, including simple excision, curettage and electrodessication (scraping with a surgical tool and treating with an electric needle) and cryosurgery (freezing with liquid nitrogen). Removing large skin cancers can require skin grafts and be disfiguring.

Sunlight can damage a skin cell’s DNA. Normally, a protein called protein kinase C (PKC) is activated in response to the damage. If the damage is too great to repair, the PKC protein directs the cell to die.

Healthy cells grow and divide in a cell-division cycle. At several checkpoints in this cycle, the cell stops to repair damaged DNA before progressing to the next step in the cycle. The new study found that the PKC gene is responsible for stopping the cell at the checkpoint just before the point when the cell divides. In squamous cell carcinoma, the PKC gene is turned off. The cell proceeds to divide without first stopping to repair its DNA, thus producing daughter tumor cells.

Denning said a class of drugs called protein kinase inhibitors potentially could shrink tumors by turning the PKC gene back on. Several such drugs have been approved by the Food and Drug Administration for other cancers. Denning is pursuing grant funding to test such drugs on animal models.

New research shows that migraine and depression may share a strong genetic component. The research is published in the January 13, 2010, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Understanding the genetic factors that contribute to these disabling disorders could one day lead to better strategies to manage the course of these diseases when they occur together,” said Andrew Ahn, MD, PhD, of the University of Florida in Gainesville, who wrote an editorial accompanying the study and is a member of the American Academy of Neurology. “In the meantime, people with migraine or depression should tell their doctors about any family history of either disease to help us better understand the link between the two.”

The study involved 2,652 people who took part in the larger Erasmus Rucphen Family study. All of the participants are descendants of 22 couples who lived in Rucphen in the 1850s to 1900s.

“Genealogical information has shown them all to be part of a large extended family, which makes this type of genetic study possible,” said study author Gisela M. Terwindt, MD, PhD, of Leiden University Medical Center in the Netherlands.

Of the participants, 360 had migraine. Of those, 151 had migraine with aura, which is when headaches are preceded by sensations that affect vision, such as seeing flashing lights, and 209 had migraine with no aura. A total of 977 people had depression, with 25 percent of those with migraine also having depression, compared to 13 percent of those without migraine.

The researchers then estimated the relative contribution of genetic factors for both of the disorders. They found that for both types of migraine, the heritability was estimated at 56 percent, i.e., 56 percent of the trait is explained by genetic effects. For migraine with aura, the estimate was 96 percent. “This finding shows that migraine with aura may be a promising avenue to search for migraine genes,” Terwindt said.

Comparing the heritability scores for depression between those with migraine and those without showed a shared genetic component in the two disorders, particularly with migraine with aura. “This suggests that common genetic pathways may, at least partly, underlie both of these disorders, rather than that one is the consequence of the other,” Terwindt said.

Older patients with acute myeloid leukemia (AML) might benefit from a drug that reactivates genes that cancer cells turn off, according to research at Washington University School of Medicine in St. Louis and collaborating institutions. The researchers say the findings support further investigation of the drug, decitabine, as a first-line treatment for these patients, who have limited treatment options.

Almost two-thirds of AML patients over age 65 do not receive treatment for the disease because standard therapy can be risky and often is ineffective. On average, such patients survive only 1.7 months after diagnosis.

“Older leukemia patients don’t have good treatment options because the chemotherapy and stem cell transplants that we commonly use for younger patients are often too toxic for them,” says lead author Amanda F. Cashen, M.D., assistant professor of medicine in the Division of Oncology and a bone marrow transplant specialist with the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

“Furthermore, the biology of acute leukemia in the older patient population is different, making their response rate lower, their risk of relapse higher and their cure rates lower,” she says. “So we definitely need new therapies in that patient population – treatments that are going to be both better tolerated and more effective.”

The study, to be published in an upcoming issue of the Journal of Clinical Oncology and now available on-line, was conducted at three sites: Washington University School of Medicine; the University of California, Los Angeles; and the City of Hope National Medical Center in Duarte, Calif. The researchers tested decitabine in 55 AML patients with an average age of 74 years.

Decitabine can increase the activity of genes that have been silenced in cancer cells. It works by reducing the amount of DNA that is marked with a chemical tag called a methyl group. Scientists think that the excess methylation found in cancer cells inactivates genes that normally suppress tumor development.

All patients received the same decitabine dose for five consecutive days every four weeks until their disease stopped responding to the drug and began progressing or until an adverse event occurred to prevent further participation. By comparison to standard chemotherapy and stem cell transplantation, the treatment was considered a low-intensity treatment and was more tolerable for elderly patients, especially those with accompanying medical problems.

In 24 percent of the study participants, blood counts and bone marrow returned to normal, which is considered a complete response. It took 4.5 cycles of decitabine treatment on average to achieve a complete response. In those with a complete response, average survival time was 14 months. For all study participants, average survival time was 7.7 months.

Treatment-related adverse events included low blood counts (red cells, white cells and platelets), infection, fever and fatigue. Almost half of the study participants had at least one serious adverse event. Seven patients discontinued treatment, and three patients died as the result of adverse events.

“We have to wait for the results of further trials of decitabine to have a better estimate of the response rate and survival outcome compared to other low intensity options for older adults,” Cashen says. “This study can’t definitively establish decitabine’s role for treating older adults with AML, but it certainly excites us to study it more.”

Two new studies showing that protein bits produced by unusual “reading” of the HIV genome can induce immune responses appeared online in the Journal of Experimental Medicine on Jan. 11.

Small, compact RNA viruses like HIV make the most of their limited genomes by stuffing genes that direct protein production into several different reading frames and orientations. When teams – led by Berger et al. at the Ragon Institute of MGH, MIT, and Harvard; and Bansal et al. at the University of Alabama – examined viral genomes in groups of HIV-infected individuals, they found an accumulation of genetic variations specifically in unusual reading frames and orientations. This finding suggested that mutations in these reading frames may have been caused by pressure from the hosts’ immune systems.

The notion was supported by their finding that HIV-infected individuals exhibited killer immune cell responses specific for protein fragments generated by unconventional reading of the HIV genome. In some cases, mutations in these reading frames allowed HIV-infected cells to escape immune cell killing.

The information provided by these findings may prove useful during future HIV vaccine design efforts.

Neuroscientists have forged an unlikely molecular union as part of their fight against diseases of the brain and nervous system.

The team has brought together the herpes virus and a molecule known as Sleeping Beauty to improve a technology known as gene therapy, which aims to manipulate genes to correct for molecular flaws that cause disease.

The work, detailed in a paper published online in Gene Therapy, has allowed scientists at the University of Rochester Medical Center to reach a long-sought goal: Shuttling into brain cells a relatively large gene that can remain on for an extended period of time.

“We’ve broken what is in effect a size barrier – a limit to how much genetic material we can put into the nucleus of a cell and keep functioning for a long period of time,” said neuroscientist William Bowers, Ph.D., a scientist in the Center for Neural Development and Disease and the leader of the team. “That opens up more diseases to possible treatment with gene therapy.”

The first author of the paper is Biochemistry graduate student Suresh de Silva, who defends his doctoral thesis later this month.

The molecular rendezvous of Sleeping Beauty and herpes in human brain cells could spell good news in the search for treatments for horrific brain diseases known as pediatric leukodystrophies, or a group of diseases known as lysosomal storage disorders. In many of these diseases, even though just a single gene or protein is defective, the effects are devastating – the diseases slowly rob children of their brain cells and are often fatal after years of severe symptoms.

The findings bolster the tools that researchers have when approaching certain diseases, said Bowers, including Usher syndrome, which results in deafness and vision loss; Niemann-Pick disease Type C, a fatal childhood lysosomal storage disorder; and von Willebrand disease, an inherited disease that causes extensive, chronic bleeding.

“The field of gene therapy is just beginning to yield some successes for patients. Improvements like this are crucial for increasing the number of patients who might benefit from such an approach,” said Bowers, who is an associate professor of Neurology, Microbiology and Immunology, and of Pharmacology and Physiology.

The research is part of a decades-long endeavor by scientists trying to get the right genes into the right cells at the right time to improve human health.

In the new work, scientists dramatically increased the size of the “genetic payload” they can deliver to brain cells compared to some conventional techniques, nearly tripling the amount of genetic material by some measures. They hope to deliver even bigger genes in the future.

The team did this by bringing together in a new way two molecular players, herpes and Sleeping Beauty, which are commonly used in molecular technology.

For years Bowers’ team has been using the herpes virus – HSV-1, the type that causes cold sores – to shuttle genes into cells. Viruses like herpes are adept at infecting human cells, and scientists like Bowers use such viruses to carry into cells genes that would help people who are sick. Bowers and colleagues modify the viruses extensively, removing the portions that could make a person sick and using the portions that the virus uses to gain access to human cells.

Many scientists use other viruses, such as lentiviruses or a cold-related virus known as adeno-associated virus (AAV), to do a similar job. Each virus has its strengths and weaknesses when it comes to gene therapy. Herpes, for instance, readily infects cells, and it can carry a huge amount of genetic material, typically 15 to 30 times the amount of DNA that other viruses can carry into a cell.

But herpes as a genetic tool has a couple of big weaknesses. While the virus can deliver DNA into the nucleus of a cell, the genetic payload it carries does not become part of the package of genes that cells pass from one to another. Simply put, herpes cannot integrate the new DNA into the host genome. Instead, the DNA is adrift in the nucleus, where it’s silenced within a few weeks. The short time span spells trouble when scientists are trying to treat a disease that requires the genes to be active for months or years.

That’s where Sleeping Beauty comes in.

In molecular biology, Sleeping Beauty is a mobile genetic element that jumps into and out of longer segments of DNA. It’s normally silent, but years ago a team of scientists was able to activate or “awaken” the snippet – hence, Sleeping Beauty. Since Sleeping Beauty actually integrates segments of DNA into mammalian genomes, it sidesteps the main difficulties that herpes encounters inside a cell: Genes integrated within the cell’s chromosomes by Sleeping Beauty operate for much longer periods of time. The drawback: The molecule can insert only small snippets of DNA.

So the Rochester team brought herpes and Sleeping Beauty together in an attempt to get the best of both worlds: Delivery of the bigger genetic package made possible by herpes, and the integration of the DNA into the host genome made possible by Sleeping Beauty.

And that’s exactly what happened. In the tag-team approach funded by the National Institute of Neurological Disorders and Stroke, herpes gets the genetic package into the right neighborhood, the cell’s nucleus, and then Sleeping Beauty delivers the package precisely where it needs to go to be most effective – into the cellular genome.

In the current experiments, the herpes virus carried into cell nuclei the gene for green fluorescent protein, which allows scientists to track where the gene is active. The team also outfitted the herpes package with special molecular signals that Sleeping Beauty would recognize. Separately, the team introduced Sleeping Beauty into the cells. When the two met, Sleeping Beauty transferred the gene for GFP from the herpes package to the genome of the human cells, where the gene was stably expressed.