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Cancer Genetics: Massive cancer gene search finds potential new targets in brain tumors

Results validate ambitious NIH-funded project to uncover cancer mutationsBOSTON--An array of broken, missing, and overactive genes -- some implicated for the first time -- have been identified in a genetic survey of glioblastoma, the most common and deadly form of adult brain cancer, report scientists from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, together with their collaborating investigators at 18 institutions and organizations.The large-scale combing of the brain cancer genome confirms the key roles of some previously known mutated genes and implicates a variety of other genetic changes that may be targets for future therapies.The findings, posted online by Nature on Thursday, Sept. 4, help solidify and expand the "parts list" of genetic flaws linked to glioblastoma multiforme (GBM), the incurable brain tumor that Sen. Edward M. Kennedy is battling. Lynda Chin, MD, at Dana-Farber and Harvard Medical School (HMS) and Matthew Meyerson, MD, PhD, at Dana-Farber, HMS, and Broad, co-led the writing effort for the first summary of data from the $100 million pilot project of The Cancer Genome Atlas (TCGA), funded by the National Institutes of Health (NIH). The data are released to the public at TCGA's website as they are generated.Systematic multi-dimensional genomic studies of patient samples of glioblastoma began in 2006 as the first TCGA program. The pilot is designed to determine the feasibility of a full-scale effort to systematically explore the universe of genomic changes involved in all types of human cancer and to demonstrate the values of such efforts in advancing cancer research and improving patient care.The current report in Nature summarizes the interim analyses of data gathered in the GBM pilot study. "The findings of significant mutations in genes that have implications for therapeutic development illustrate precisely how unbiased and systematic cancer genome analyses can lead to paradigm-shifting discoveries," said Chin, who chairs the GBM disease working group within TCGA.An exciting example, Chin said, is an unanticipated observation of a link between DNA methylation of specific genes and DNA repair defects, leading to a hypothesis about a potential mechanism of resistance to a common chemotherapy drug used for brain cancer.The Nature paper complements a parallel study by Johns Hopkins researchers of 22 GBM tumors, which was also published on Sept. 4 in the journal Science."These data show that this approach, of looking at large numbers of tumors and a large number of genetic factors, can be done and the results are really valuable," said Meyerson. "We have made significant novel findings, and the reproducibility of the data is high."Collaborating teams analyzed 206 specimens of glioblastoma tissue donated by patients at four medical centers. Their approach was "multidimensional" -- looking for several categories of flaws simultaneously. These included mutations -- "typos" in the DNA code of a gene that alters its function; too many or too few copies of a given gene; damage to chromosomes causing loss or dislocation of pieces; gene activity that is higher or lower than normal; and changes in DNA methylation -- turning genes on or off without affecting their structure.The researchers also had access to information on how the patients who donated the samples had fared, including how they responded to certain drugs.Automated machines at three Genome Sequencing Centers, including the Broad Institute center led by Eric S. Lander, Broad Institute director, were set to work reading the DNA messages in the cancer cells' nuclei. Of the roughly 20,000 protein-coding genes in the tumor cells, 601 genes were selected by the GBM disease working group for detailed sequencing -- determining the order of chemical "letters" in the DNA -- and comparison. A second installment of genes is already being sequenced, and Chin and her group are working on additional gene lists for mutational analyses.Five major gene mutations have previously been identified in glioblastoma cells; the new sequencing effort revealed three that hadn't been discovered. One mutation affects the NF1 gene, which causes neurofibromatosis. A second mutation is in the ERBB2 gene known to be involved in breast cancer. The third affects a gene in the PIK3 signaling pathway that is abnormally activated in a number of cancers, but this particular gene, PIK3R1, had been only rarely implicated in any cancer. "Each of these mutated genes defines a new target for glioblastoma treatment," said Meyerson.As they examined the data, the researchers found that three signaling pathways -- networks of genes and proteins that act together to carry out a cellular function -- were disrupted in more than three-quarters of the GBM tumors. They are known as the cyclin-dependent kinase/retinoblastoma pathway that regulates cell division; the p53 tumor suppressor pathway, which is involved in response to DNA damage and cell death; and the receptor tyrosine kinase pathway that carries signals that control cell growth.Chin said that the most exciting finding is that this multipronged study design also enabled the scientists to make a potentially important connection between a methylation change in the glioblastoma cells and which drugs should be used for treatment. Brain tumors that contain a methylated, or silenced, form of a gene known as MGMT are known to be more susceptible to cancer drug temozolomide (Temodar). Therefore, Temodar is routinely given along with radiation to patients with MGMT methylation.But the analysis of methylation in the glioblastoma tumors, when matched with the patients' medical history, revealed a cautionary sign. When such patients were treated with Temodar and subsequently had a recurrence of the tumor, it was very likely to become resistant to treatment because of "hypermutation" -- an increased rate of gene changes that led to the tumor's ability to evade the drugs."This could have immediate clinical applications," said Chin.The discoveries in the paper are only the tip of an expected iceberg, said the authors. The "most powerful impact" is expected to come from further research studies carried out by scientists who make use of the data released freely by TCGA, they said.More than 21,000 new cases of brain cancer are expected to be diagnosed in the United States this year, and more than 13,000 people are likely to die from the disease."These impressive results from TCGA provide the most comprehensive view to date of the complicated genomic landscape of this deadly cancer," said NIH Director Elias A. Zerhouni, M.D. "The more we learn about the molecular basis of glioblastoma multiforme, the more swiftly we can develop better ways of helping patients with this terrible disease. Clearly, we should move ahead and apply the power of large-scale, genomic research to many other types of cancer."Chin is co-principal investigator of a TCGA center with Raju Kucherlapati of HMS, and Meyerson is principal investigator of a TCGA Cancer Genome Characterization Center at the Broad Institute. Chin is the scientific director of the Belfer Cancer Genomics Center in the Center for Applied Cancer Science at Dana-Farber, and Meyerson directs the Center for Cancer Genome Discovery at Dana-Farber.The research was funded by grants from the NIH.Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.The Broad Institute of MIT and Harvard was founded in 2003 to bring the power of genomics to biomedicine. It pursues this mission by empowering creative scientists to construct new and robust tools for genomic medicine, to make them accessible to the global scientific community, and to apply them to the understanding and treatment of disease. The Institute is a research collaboration that involves faculty, professional staff and students from throughout the MIT and Harvard academic and medical communities. It is jointly governed by the two universities. Organized around Scientific Programs and Scientific Platforms, the unique structure of the Broad Institute enables scientists to collaborate on transformative projects across many scientific and medical disciplines. For further information about the Broad Institute, go to http://www.broad.mit.edu.

Researchers Find Mechanism To Target Brain Tumor Cells

Researchers at Duke University Medical Center and the University of North Carolina, Chapel Hill are exploiting an "Achilles Heel" of brain tumors that may selectively kill tumor cells while sparing surrounding brain tissue. Although most cancer cells thrive by avoiding the normal process of programmed cell death, or apoptosis, the researchers found a way to turn this normal cell suicide way up for brain cancer cells. "In collaboration with Dr. Deshmukh's lab at UNC, we attempted to come up with a way to specifically target tumor cells without damaging surrounding cells," said Sally Kornbluth, Ph.D., Professor of Pharmacology and Cell Biology and Vice Dean of Basic Sciences. In addition to turning off normal cell death, brain cancers, such as glioblastomas and medulloblastomas, are generally resistant to traditional chemotherapy. And chemotherapy and radiation can also lead to significant neurological defects because they kill both cancerous and healthy brain. In their study, published in the December issue of the Proceedings of the National Academy of Sciences, the researchers found that brain tumor cells are particularly sensitive to a protein called cytochrome c, which is involved in programmed cell death. Because of this difference, lab-cultured, human brain tumor cells treated with cytochrome c were killed, while mature neurons were not affected. "This work highlights a previously unappreciated vulnerability within tumor cells. It also suggests a powerful technique by which new chemotherapeutic agents could act," Kornbluth said. "Apoptosis could be induced within brain tumors by small molecules that mimic cytochrome c," said Mohanish Deshmukh of UNC, co-seniorauthor of the study. All types of brain tumors appear to share this vulnerability, Kornbluth said. The next step toward a real-world treatment would be to determine how to deliver cytochrome c directly to brain cells without affecting other cells in the body. Indeed, much of conventional chemotherapy's more debilitating side effects, including extreme fatigue and low blood-cell counts, come from the inadvertent elimination of healthy cells. The study was supported by grants from the National Institutes of Health and the Pediatric Brain Tumor Foundation.

Role of Hypnosis in Surgical Recovery for Patients with Head and Neck Cancer

Surgery is a very common occurrence in the United States. Surgeries are performed to diagnose and/or treat a condition. The three major concerns with any type of surgery are pain, bleeding, and infection. Taking small steps such as mandating hypnotherapy sessions for patients going through such tough procedures can have beneficial affects on both the patients’ physical and mental well-being, along with their finances.A study was performed in 1991 involving 36 patients who had head and neck cancer and were undergoing surgery to treat it. An article about the study appeared in the International Journal of Clinical and Experimental Hypnosis. The study was conducted to see whether hypnosis played a role in recovery after surgery for patients suffering from 2 particular types of cancers.The study consisted of 36 participants who were diagnosed with head and neck cancer and were undergoing surgery. Twenty-one patients served as the control group and received no hypnosis. Fifteen patients received hypnotherapy. The researchers wanted to compare length of hospital stay, surgical complications, and blood loss between the hypnosis group and the control group.Results from this study were significant between the two groups. Researchers found that those who received hypnotherapy had a much shorter hospital stay than the control group who received standard care.Researchers also found some differences among the group that received hypnosis. Those who were more highly hypnotizable experienced fewer complications after the surgery. Also, the researchers found that those who were more hypnotizable also had less blood loss during the surgery.The study concluded that hypnosis can help prevent postoperative complications. A reduction in complications after surgery also reduces the length of hospital stay after the operation. Fewer complications also suggest a quicker recovery time. A shorter hospital stay means lower medical bills.Patients going through cancer treatment already experience a high level of stress and anxiety with rehabilitation. Hypnotherapy ensures that the healing time and treatment period is shorter and more easily dealt with. The procedure may not only show physical improvements, but emotional ones as well. By taking such a small step, doctors can now further help improve the lives of their patients. Financial, physical, and emotional strains may be lifted with the help of hypnotherapy.

New Evidence Linking Meat To Cancer

Diets high in red and processed meats have long been associated with cancer of the large intestine. Now, however, for the first time scientists have looked at whether eating meat and other animal fats is also linked to cancers of the small intestine. Their findings show yet again what natural health advocates have said for years: red meat and diets high in animal fats are a good way to promote cancer, not wellness.The new study, just published in the Cancer Research, a journal of the American Association for Cancer Research, strongly suggests eating diets high in meat and other saturated fats is associated cancer of the small intestine -- a kind of cancer that has been steadily increasing since the l970s. If a person gets this type of cancer, they are at increased risk of also developing a second malignancy, an often deadly colorectal cancer."Identifying modifiable risk factors for cancer of the small intestine is important not only because the incidence of this cancer is on the rise, but it may enable us to further understand other gastrointestinal malignancies," Amanda Cross, Ph.D., a National Cancer Institute researcher and the study’s lead author, said in a statement to the media.Cross and her research team used food frequency questionnaires to document the food intake of a half million men and women enrolled in the NIH -AARP ( National Institutes of Health and American Association of Retired People) Diet and Health study over about eight years. Their findings strongly indicate the risk for a type of tumor called a carcinoid in the small intestine was associated with consuming saturated fats. Carcinoid tumors are a slow-growing type of cancer that can arise in several places throughout the body but are most often found in the gastrointestinal tract. They produce and release hormones into the body that cause symptoms such as diarrhea or skin flushing but these problems rarely show up until late in the disease.“There is some evidence to suggest that cancers of the small and large bowel both arise from adenomatous polyp precursor lesions, suggesting the adenoma-carcinoma sequence is relevant to both sites. For unknown reasons, the large intestine is much more susceptible to malignant transformation. Identifying risk factors that are unique as well as those that are similar for the two sites may aid our understanding of the comparative resistance of the small intestine to carcinogenesis,” Cross said in the press statement.She added that the associations found in the new study need to be studied further in other populations and with different types of saturated fat in order to understand the potential mechanisms involved.More cancer and saturated fat news: a study by scientists at the Tuft School of Medicine recently published in the journal Nutrition and Cancer concludes a low-fat diet may play a significant role in preventing breast cancer. The bottom line? Evidence continues to mount that by eating a diet centered on fruits and vegetables instead of fat-laden animal products, you can help control your risk of developing cancer.

Breast Cancer Rates Soar after Mammograms and Some Cancers may Heal Naturally

A report just published in the Journal of the American Medical Association's Archives of Internal Medicine (Arch Intern Med. 2008;168[21]:2302-2303) reaches a startling conclusion. Breast cancer rates increased significantly in four Norwegian counties after women there began getting mammograms every two years. In fact, according to background information in the study, the start of screening mammography programs throughout Europe has been associated with increased incidence of breast cancer.This raises some obvious and worrisome questions: Did the x-rays and/or the sometimes torturous compression of breasts during mammography actually spur cancer to develop? Or does this just look like an increase in the disease rate because mammography is simply identifying more cases of breast cancer?The answer to the first question is that no one knows (and it isn't addressed in the Archives of Internal Medicine study). But the second question has an unexpected and – for those interested in the human body's innate ability to heal itself – potentially paradigm-shifting answer. The researchers say they can't blame the increased incidence of breast cancer on more cases being found because the rates among regularly screened women remained higher than rates among women of the same age who only received mammograms once after six years. Bottom line: the scientists conclude this indicates that some of the cancers detected by mammography would have spontaneously regressed if they had never been discovered on a mammogram and treated, usually with chemotherapy and radiation. Simply put, it appears that some invasive breast cancers simply go away on their own, healed by the body's own immune system.Per-Henrik Zahl, M.D., Ph.D., of the Norwegian Institute of Public Health, Oslo, and his research team studied breast cancer rates among 119,472 women (age 50 to 64). These research subjects were asked to participate in three rounds of screening mammograms between 1996 and 2001, as part of the Norwegian Breast Cancer Screening Program. The scientists then compared the number of breast cancers found in this group to the rate of malignancies among a control group of 109,784 women who were the same ages in 1992, and who would have been invited for breast screenings if the program had been in place that year. Cancers were tracked using a national registry. Then, after six years, all participants were invited to undergo a one-time screening to assess for the prevalence of breast cancer.The researchers were surprised to find that the incidence of invasive breast cancer was 22 percent higher in the group regularly screened with mammography. In fact, screened women were more likely to have breast cancer at every age."Because the cumulative incidence among controls never reached that of the screened group, it appears that some breast cancers detected by repeated mammographic screening would not persist to be detectable by a single mammogram at the end of six years," the authors stated in their report. "This raises the possibility that the natural course of some screen-detected invasive breast cancers is to spontaneously regress."The researchers also conclude that their findings "provide new insight on what is arguably the major harm associated with mammographic screening, namely, the detection and treatment of cancers that would otherwise regress."This does not mean breast cancer should be ignored or not treated. After all, breast cancer is the second leading cause of death among American women. But the extraordinarily good and hopeful news is that it appears invasive breast cancer sometimes can be destroyed naturally -- at least in some people -- by the body's own innate defenses."Although many clinicians may be skeptical of the idea, the excess incidence associated with repeated mammography demands that spontaneous regression be considered carefully," the scientists wrote in their report. "Spontaneous regression of invasive breast cancer has been reported, with a recent literature review identifying 32 reported cases. This is a relatively small number given such a common disease. However, as some observers have pointed out, the fact that documented observations are rare does not mean that regression rarely occurs. It may instead reflect the fact that these cancers are rarely allowed to follow their natural course."In an editorial in the Archives of Internal Medicine that accompanies the breast cancer study, Robert M. Kaplan, Ph.D., of the University of California, Los Angeles, and Franz Porzsolt, M.D., Ph.D., of Clincal Economics University of Ulm, Germany, wrote that the most important concern raised by the study is "how surprisingly little we know about what happens to untreated patients with breast cancer.In addition to not knowing the natural history of breast cancer for younger women, we also know very little about the natural history for older women. We know from autopsy studies that a significant number of women die without knowing that they had breast cancer (including ductal carcinoma in situ). The observation of a historical trend toward improved survival does not necessarily support the benefit of treatment