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July 14, 2009JAMA news releases are made available to the public after 3 pm US Central time on the first 4 Tuesdays of each month. The Archives of Journals news releases are made available to the public after 3 pm Central time on Mondays. We also provide a list of previous news releases. THIS WEEK'S CONTENTS
JAMA NEWS RELEASES
(Embargoed for Release: 3 p.m. CT Tuesday, July 14, 2009)
JAMA REPORT (VIDEO SCRIPT)
INFORMATION CONTAINED IN THESE NEWS RELEASES IS PROTECTED BY COPYRIGHT. JOURNAL ATTRIBUTION IS REQUIRED. JOURNALISTS CAN NOW ACCESS EMBARGOED JAMA/ARCHIVES STUDIES ON-LINE. Go to www.jamamedia.org for more information and to apply for access. TV Note: PLEASE NOTE, FEED TIMES ARE NOW 15 MINUTES. This week's JAMA Report video is on the identification of altered genes that appear to play a role in the development of brain tumors. The report will be fed Tuesday, July 14, from 9:00 - 9:15 a.m. ET and 2:00 - 2:15 p.m. ET, on Galaxy 28 (C-Band), Transponder 19, downlink frequency: 4080 vertical, audio 6.2/6.8. For more information, call 312/464-JAMA. The JAMA Report video is also now available on Pathfire every Tuesday. Please look for the JAMA Report "channel". Please Note: The FOR THE MEDIA website now has a search feature to enable media to find previous JAMA/Archives news releases on specific medical topics. This search feature link is located on the home page at www.jamamedia.org EMBARGOED FOR RELEASE UNTIL 3 P.M. (CT), Tuesday, July 14, 2009
Research Identifies Network of Altered Genes That Appear to Play Role in Development of Brain Tumors
CHICAGO—The interaction between a network of altered genes appears to play an important role in the development and progression of brain tumors, according to a study in the July 15 issue of JAMA. Malignant gliomas (brain tumors) are associated with disproportionately high illness and death and are among the most devastating of tumors. Particular genomic alterations are fundamental to both their formation and their malignant progression. "Chromosomal alterations presumably exert their tumor-promoting effect on glioma cells by modifying the expression or function of distinct genes, which map to those alterations, so as to deregulate growth factor signaling and survival pathways. For many chromosomal alterations, the biologically relevant target genes remain to be discovered," the authors write. Oncogenic research on brain tumors has focused on the tumor-promoting or tumor-suppressive function of target genes within individual chromosomal alterations. However, these alterations do not exist in isolation, nor do single genes account for gliomagenesis. Rather, there may be mechanistic links to genes at other, coincident alterations, according to background information in the article. Markus Bredel, M.D., Ph.D., of the Northwestern Brain Tumor Institute at Northwestern University Feinberg School of Medicine, Chicago, and colleagues examined the relationships of tumor-promoting genes in gliomas. The study included genomic profiles and clinical profiles of 501 patients with gliomas (45 tumors in an initial discovery set collected between 2001 and 2004 and 456 tumors in validation sets made public between 2006 and 2008) from multiple academic centers in the United States and The Cancer Genome Atlas Pilot Project (TCGA). The analysis included the identification of genes with coincident genetic alterations, correlated gene dosage (the copy number for a specific gene determined by certain analytic approaches) and gene expression, and multiple functional interactions; and the association between those genes and patient survival. The researchers found: "The alteration of multiple networking genes by recurrent chromosomal aberrations in gliomas deregulates critical signaling pathways through multiple, cooperative mechanisms. These mutations, which are likely due to nonrandom selection of a distinct genetic landscape [a consistent pattern of chromosomal alterations] during gliomagenesis, are associated with patient prognosis." The authors add that the identification of such gene alterations in gliomas prompts evaluation of their potential as therapeutic targets. "The network context of a gene likely affects the efficacy of therapies that target its protein. The complexity of our landscape model helps explain the lack of therapeutic efficacy of strategies targeting single gene products." A multigene risk scoring model based on seven landscape genes was associated with the duration of overall survival in 189 glioblastoma patients from TCGA, an association that was confirmed in three additional malignant glioma patient populations.
"The current work provides a network model and biological rationale for the selection of a nonrandom genetic landscape in human gliomas," the authors write. "A multigene predictor model incorporating 7 landscape genes demonstrates how molecular insights emerging from our integrative multidimensional analysis could translate into relevant clinical end points affecting the future management of gliomas."
Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. Study Examines Mechanism for Gene Alterations in Brain Tumors
In a related article appearing in the July 15 issue of JAMA, researchers have identified the mechanism linked to the alteration of certain genes cited by Bredel et al in the previous study. Glioblastomas-uniformly fatal brain tumors-often have both monosomy (absence of 1 chromosome) of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7. This association suggests a fundamental biological role in glioblastoma pathogenesis, yet its molecular basis is poorly understood, according to background information in the article. Markus Bredel, M.D., Ph.D., of the Northwestern Brain Tumor Institute at Northwestern University Feinberg School of Medicine, Chicago, and colleagues examined the mechanism of deregulation of the gene ANXA7 in glioblastomas and its association with patient outcome. The study included a multidimensional analysis of gene, coding sequence, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from U.S. medical centers and The Cancer Genome Atlas pilot project. The authors write: "We propose that ANXA7 haploinsufficiency [when a diploid cell (a cell having two sets of chromosomes) only has a single functional copy of a gene that does not produce enough of a gene product (typically a protein) to permit the cell to function normally, leading to an abnormal or diseased state] is a positive regulator of EGFR signaling and a driver for the conserved monosomy of chromosome 10 in glioblastomas. We provide evidence that ANXA7 loss of function facilitates unmitigated EGFR signaling, thereby contributing to an EGFR gain-of-function phenotype in high-grade gliomas, and that the complementary dysregulation of EGFR and ANXA7 synergistically promotes the tumorigenic potential of glioblastoma cells." The authors found that the status of the ANXA7 gene was immediately associated with the duration of survival of malignant gliomas in three patient populations.
"The dismal prognosis in glioblastoma outcome, even with the most advanced clinical care, addresses the need for the translation of new biological insights into clinical end points that can ultimately influence patient management. Identification of genes in which expression is altered or pathways in which activity is modified in tumors is important to understanding basic tumor biology, developing clinical-pathological correlations, and identifying points of therapeutic intervention. As we demonstrate here for ANXA7 and its link to EGFR signaling and dysregulation in glioblastomas, these require integration of genomic analysis, cancer genetics and biology, and clinical validation."
Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. Editorial: One Step Forward Toward Identification of the Genetic Signature of Glioblastomas
In an accompanying editorial, Boris Pasche, M.D., Ph.D., of the University of Alabama at Birmingham, and UAB Comprehensive Cancer Center, Birmingham, and Contributing Editor, JAMA, and Richard M. Myers, Ph.D., of the HudsonAlpha Institute for Biotechnology, Huntsville, Ala., comment on the findings of the studies in this week's JAMA on genetics and brain tumors. "The potential clinical implications of these findings are significant. First, they highlight a pattern of codependent genetic interactions, which will need to be taken into account when designing novel therapeutic interventions in this otherwise therapy-refractory disease. Second, they provide a novel prognostic tool that may guide future therapeutic interventions."
"These 2 articles on glioblastoma multiforme are just the beginning, and many more reports on other cancers and other diseases are expected to be available in the near future; indeed, the amount of data and comprehensiveness of covering of the whole genome in such studies are expected to rapidly increase as the new DNA sequencing technologies improve even more. Once the new alphabet of these tumors is known, scientists will have the capability to decipher the language, which will usher in a new era in cancer research."
Editor's Note: Please see the article for additional information, including financial disclosures, funding and support, etc. For more information, contact JAMA/Archives media relations at 312/464-JAMA (5262) or e-mail mediarelations{at}jama-archives.org. EMBARGOED FOR RELEASE UNTIL 3 P.M. (CT), Tuesday, July 14, 2009
Hormone Therapy Use Associated With Increased Risk of Ovarian Cancer
CHICAGO—Compared with women who have never taken hormone therapy, those who currently take it or who have taken it in the past are at increased risk of ovarian cancer, regardless of the duration of use, the formulation, estrogen dose, regimen or route of administration, according to a study in the July 15 issue of JAMA. Primary prevention of ovarian cancer is challenging because little is known about its cause. Studies have suggested an increased risk of ovarian cancer among women taking postmenopausal hormone therapy (HT), according to background information in the article. Data have been limited on the differing effects of formulations, regimens and routes of administration. Lina Steinrud Mørch, M.Sc., of Rigshospitalet, Copenhagen University, Denmark, and colleagues conducted a study to examine the risk of ovarian cancer associated with hormone therapy use. The study included all Danish women age 50 through 79 years from 1995 through 2005 through linkage to Danish national registers. Prescription data from the National Register of Medicinal Product Statistics provided individually updated information on HT use. The National Cancer Register and Pathology Register provided ovarian cancer incidence data. The analysis included a total of 909,946 women without hormone-sensitive cancer or who had not had both ovaries removed. At the end of follow-up, 63 percent of the women had not been taking HT, 22 percent were previous users of hormones, and 9 percent current users of hormones. Among the current users, 46 percent had used hormones for more than 7 years. During an average of 8 years of follow-up, 3,068 ovarian cancers were detected . Of these, 2,681 were epithelial tumors (a type of ovarian cancer). Compared with never users, current users of HT had an overall 38 percent increased risk of ovarian cancer. When restricting the analyses to epithelial ovarian cancer, the relative risk among current HT users was 44 percent higher, with previous HT users having a 15 percent increased risk compared with women who had never used HT. The risk for ovarian cancer and epithelial ovarian cancer did not increase significantly with increasing durations of HT. The risk of ovarian cancer declined with longer time since last HT use. The risk of ovarian cancer did not differ significantly by formulation, regimen, type of progestin or route of administration.
The absolute risk indicated approximately 1 extra ovarian cancer for roughly 8,300 women taking hormone therapy each year. "If this association is causal, use of hormones has resulted in roughly 140 extra cases of ovarian cancer in Denmark over the mean follow-up of 8 years, i.e., 5 percent of the ovarian cancers in this study. Even though this share seems low, ovarian cancer remains highly fatal, so accordingly this risk warrants consideration when deciding whether to use HT," the authors write.
Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. For more information, contact JAMA/Archives media relations at 312/464-JAMA (5262) or e-mail mediarelations{at}jama-archives.org. EMBARGOED FOR RELEASE UNTIL 3 P.M. (CT), Tuesday, July 14, 2009
Repair of Heart Defect Discovered Incidentally During Surgery May Not Have Clear Benefit
CHICAGO—Patients who have a heart defect known as patent foramen ovale incidentally discovered and repaired during surgery for a different condition may have an increased odds of postoperative stroke, along with no clear benefit on short-term outcomes or long-term survival, according to a study in the July 15 issue of JAMA. Patent foramen ovale (PFO) is an opening in the upper chambers of the heart that failed to close naturally shortly after birth. The role that PFO plays in cryptogenic (of unknown cause) stroke remains controversial. "The debate over an association has existed for more than a century, but causal data linking PFO and cryptogenic stroke remain anecdotal. Epidemiological evidence is consistent with an increased risk of stroke associated with PFO but data are not conclusive. The paucity of evidence supporting PFO as the mechanism for cryptogenic stroke has left many questions in the field unanswered, including when PFO repair is appropriate," the authors write. A recent survey suggested that cardiothoracic (heart and chest) surgeons may alter planned procedures to repair a newly discovered PFO. How frequently this occurs and the impact on outcomes has been unknown, according to background information in the article. Richard A. Krasuski, M.D., of the Cleveland Clinic, and colleagues examined the prevalence of PFO incidentally discovered during cardiothoracic surgery and investigated the relationship of repair (closure of the opening) on outcomes and long-term survival. The researchers reviewed the intraoperative transesophageal (through the esophagus) echocardiograms of 13,092 patients without prior diagnosis of PFO or atrial septal defect (an abnormal opening between the left and right atria of the heart) undergoing surgery at the Cleveland Clinic from 1995 through 2006. Postoperative outcomes were collected until discharge. The authors found that PFO was intraoperatively discovered in 2,277 patients (17 percent). Of patients with newly discovered PFO, 639 (28 percent) underwent surgical repair, nearly all of which were suture closures (97 percent). Patients undergoing repair were more likely to be women, be younger, have a history of stroke or atrial fibrillation. Further analysis indicated that patients with intraoperatively diagnosed PFO had similar rates of in-hospital stroke and hospital death. Length of hospital stay and days spent in the ICU were also similar between those with intraoperatively diagnosed PFO and those without. Regarding outcomes for patients who underwent PFO repair compared with those who did not, the primary difference noted between the 2 groups was the rate of in-hospital stroke, which was 2.8 percent in the repaired group vs. 1.2 percent in the unrepaired group, representing a nearly 2.5 times greater odds of having in-hospital stroke. The rate of hospital deaths, hospital length of stay, ICU length of stay and time on cardiopulmonary bypass were all similar. Long-term analysis demonstrated that PFO repair was associated with no survival difference.
"In summary, PFO is commonly detected during intraoperative imaging at the time of cardiothoracic surgery. When incidentally discovered, it appears to have a benign short-term and long-term clinical course. While the number of events is small, there was no clear benefit of closure on short-term perioperative outcomes or longer-term mortality. The finding that repair may increase postoperative stroke risk should discourage routine surgical closure and foster further investigation to delineate whether there is any benefit in terms of long-term stroke prevention and which patients might benefit from this intervention," the authors conclude.
Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. For more information, contact JAMA/Archives media relations at 312/464-JAMA (5262) or e-mail mediarelations{at}jama-archives.org.
JAMA REPORTS
VIDEO: Windows Media | Quicktime
SCIENTISTS FIND ALTERED GENES ASSOCIATED WITH A DEADLY BRAIN TUMOR
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