Carcinogenesis

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Flibanserin produced significant improvement not only in the FSFI 'desire' domain, but also across the other domains of sexual function assessed by the FSFI. Low Serum Testosterone is Associated with Increased Stress and Mixed Incontinence in Women (#PD50-07): The association between testosterone levels and urinary incontinence has not been extensively studied, which is why  researchers examined the relationship between testosterone levels and self- reported urinary incontinence in women. Data from 2,123 females who self- reported stress, urge or mixed urinary incontinence as part of the 2012 cycle of National Health and Nutrition Examination Survey, and who also underwent measurement of their testosterone levels, were analyzed. Researchers first  examined each participant's testosterone levels in a weighted variance-corrected univariate model for association with incontinence, and then in a weighted variance-corrected model adjusted for age, body mass index, diabetes, race, parity and the time of day their blood was drawn for testosterone level measurement. Investigators concluded that given the role of pelvic musculature in maintaining urethral support and the anabolic effect of androgens on skeletal muscle, a physiologic mechanism for this relationship could be proposed and further evaluated in prospective and translational studies. Is Vaginal Mesh a Stimulus of Autoimmune Disease (#PD17-08) and Transvaginal Mesh Does Not Cause Carcinogenesis (#PD02-10): Two separate studies refuted claims against mesh as a cause of systemic disease and a cause of cancer. In the first study, researchers looked for the potential link between the development of systemic/autoimmune disorders and synthetic polypropylene mesh repairs. A total of 2,257 patients who underwent mesh based pelvic organ prolapse (POP) surgery were analyzed. When patients were matched, based on demographics, comorbities and procedure time, mesh-based surgery was not associated with an increased risk of developing autoimmune disease. Similarly, in the second study, an investigation sought to find a potential link between carcinogenesis and synthetic polypropylene mesh repairs using statewide administrative data. A total of 2,301 patients who underwent mesh based POP surgery were analyzed. The results showed mesh-based surgery was not associated with an increased risk of developing a cancer diagnosis at 1-year and during the entire follow up of up to 5 years. "These studies show promise in understanding more about a woman's sexual and urologic health" said Tomas L. Griebling, MD, MPH, AUA spokesperson and session moderator. "The favorable outcomes associated with such new treatments as Flibanserin, as well as data indicating synthetic vaginal mesh does not cause either systematic disease or cancer, are important factors in patient diagnosis, treatment and survival variances and is beneficial information for physicians to discuss with their patients." NOTE TO REPORTERS: Experts are available to discuss this study outside normal briefing times. To arrange an interview with an expert, please contact the AUA Communications Office at 410-689-3932 or e-mail . About the American Urological Association: The 112th Annual Meeting of the American Urological Association takes place May 12 – 16 at the Boston Convention & Exhibition Center in Boston, MA. Founded in 1902 and headquartered near Baltimore, Maryland, the American Urological Association is a leading advocate for the specialty of urology, and has more than 21,000 members throughout the world. The AUA is a premier urologic association, providing invaluable support to the urologic community as it pursues its mission of fostering the highest standards of urologic care through education, research and the formulation of health policy. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/female-pelvic-health-panel-investigates-a-medication-for-hsdd-low-serum-testosterones-association-with-sui-and-issues-surrounding-transvaginal-and-vaginal-mesh-300456691.html


News Article | May 18, 2017
Site: www.businesswire.com

CHAPEL HILL, N.C.--(BUSINESS WIRE)--Bell Leadership Institute, a recognized leader in leadership training and executive development, is pleased to introduce Jon S. Player, J.D., M.S.P.H. as the newest leadership trainer and coach on its expanding team. Jon is a natural presenter who sharpened his skills before judges and juries and brings his varied experiences to delivering Dr. Gerald D. Bell’s mission to create world-class leaders. Prior to joining Bell Leadership Institute, Jon practiced law as a civil litigator in North Carolina for nine years. Clients sought his counsel on the most complex cases as well as for his measured approach to dispute resolution. His work as a trial attorney provides him a unique perspective for training leaders, especially in companies who are undergoing dramatic change. Jon takes an investigative approach to identify and analyze issues that hinder growth, breaking down complex situations into essential, manageable elements while looking for specific and targeted solutions. Before practicing law, Jon managed large-scale University research studies investigating the role of genetics in cancer development. He also lived in Guatemala volunteering for Mercy Ships, a medical organization that provides medical, optical and dental treatments for indigenous populations. Jon received his BS (Biology) and master’s degree (Environmental Health) from the University of North Carolina at Chapel Hill, where his research was published in peer review journals: Breast Cancer Research, Carcinogenesis, and Cancer Causes and Control. He received his law degree from the University of Richmond in Virginia. While there, he assumed the role of Editor in Chief of the Richmond Journal of Law and Technology, as well as helped the University to start the Institute for Actual Innocence, which focuses on the exoneration of wrongly convicted prisoners in Virginia. “I’ve seen firsthand how leadership can make a profound difference in how organizations react to problems and opportunities. Dr. Bell’s lifelong work on leadership has helped countless people become more effective, build organizations, and lives. It’s an honor that Dr. Bell asked me to join Bell Leadership and I am thrilled to have the opportunity to work with him to carry those lessons forward,” said Jon Player. Jon is ready to hit the ground running with leading onsite training sessions including Bell’s cornerstone AchieversTM program. For booking availability and fees, please contact Amy Hagen with Bell Leadership at (919) 967-7904. Bell Leadership Institute is a recognized leader in leadership training and executive education. Since 1972, Bell Leadership has helped organizations develop leadership mastery through its programs and services. Its training programs have been used by more than 500,000 leaders in more than 5,000 organizations in over 50 countries.


News Article | May 17, 2017
Site: www.chromatographytechniques.com

A University of Colorado Cancer Center clinical trial is now recruiting prostate cancer patients who would otherwise be on a watch-and-wait protocol to test the ability of grape seed extract to slow the rise of prostate-specific antigen (PSA), a common marker of prostate cancer progression. The trial is the result of a series of CU Cancer Center studies demonstrating the promise of grape seed extract in preclinical models of prostate cancer, in collaboration with doctors at University of Colorado Hospital who treat the condition. In addition to testing grape seed extract, the trial provides the framework to test other promising compounds in this setting, potentially including additional compounds derived from natural sources. "In this window, we would only be watching these patients - our trial is an alternative to observation, not an alternative to treatment - and we've shown that grape seed extract is unlikely to cause side effects. So why not take this opportunity to test some of these promising compounds, starting with grape seed extract?" says Paul Maroni, MD, investigator at the CU Cancer Center and associate professor of Surgery at the CU School of Medicine. The trial will enroll 40 men with asymptomatic, non-metastatic prostate cancer with rising PSA, who will take 150 mg of grape seed extract by mouth twice daily. These men will then be evaluated every 6 weeks for a year to measure the progress of their cancer. "Our hope it that the PSA will not rise as quickly as it has in the past for this patient," says Maroni. "If we would expect it to go from 1 to 2 in next six months, but it only goes up to 1.5 in the grape seed extract group, that would be a significant improvement. This might help them avoid needing other treatments with side effects." Because prostate cancer tends to be an especially slow-growing form of the disease, it may only take slowing the disease's acceleration by a small amount to push back the date at which the cancer would be expected to become problematic far past a patient's predicted lifespan. "For many prostate cancer patients, the goal is to die with the disease rather than from it. We see the potential for grape seed extract to help us reach this goal," Maroni says. His optimism is built largely on the laboratory work of CU Cancer Center investigator Rajesh Agarwal, PhD, professor in the CU Skaggs School of Pharmacy and Pharmaceutical Sciences. Agarwal's lab has primarily focused on using the tools of molecular medicine to evaluate compounds derived from natural products in the same ways that researchers would evaluate any promising anti-cancer agent. For example, Agarwal's 2012 paper in the journal Carcinogenesis shows that grape seed extract creates oxidative stress that damages cancer cell DNA and also interrupts the pathways that would repair this damage (as seen by decreased levels of the DNA repair molecules Brca1 and Rad51 and DNA repair foci). A 2015 paper in the journal Molecular Carcinogenesis looks even closer at this mechanism to show how grape seed extract initiates this oxidative stress, namely by targeting the energy-producing mitochondria in cancer cells. Another 2015 paper, in Current Cancer Drug Targets, shows that grape seed extract targets prostate cancer progenitor cells by slowing their ability to grow new blood vessels needed to supply the cancer with nutrients. "I think the whole point is that cancer cells have a lot of defective pathways and they are very vulnerable if you target those pathways. The same is not true of healthy cells," Agarwal says. The Agarwal lab has followed this line of reasoning to show that grape seed extract does indeed use these mechanisms to slow the growth of cancers in mouse models, setting the stage for the current clinical trial which will test, for the first time, the effect of grape seed extract in human cancer patients. In fact, ongoing work at the Agarwal lab is unpacking mechanics of a few other compounds derived from natural sources including milk thistle extract and bitter melon. "Ultimately, if grape seed doesn't change how we approach these patients, then we've built a program to examine other complimentary or low-side-effect medicines. If grape seed extract doesn't work, we can take this protocol, put in a new background - bitter melon, milk thistle, etc. - and examine that," Maroni says. Many drugs currently used against cancer originated from substances found naturally. Now this approach that uses the tools of Western medicine to evaluate what some would consider Eastern ideas may allow doctors to add to this list of naturally-derived compounds that aid our fight against cancer.


News Article | November 17, 2016
Site: www.eurekalert.org

Glioblastoma multiforme remains the most common and highly lethal brain cancer and is known for its ability to relapse. Researchers at The University of Texas MD Anderson Cancer Center have identified a pathway by which cancer cells aggressively spread and grow in the brain, opening up new possibilities for treatment. Study findings were published in the Nov. 17 online version of Cell. Co-authors included Baoli Hu, Ph.D., senior research scientist, Y. Alan Wang, Ph.D., associate professor, and Ronald A. DePinho, M.D., professor, all of Cancer Biology, and Qianghu Wang Ph.D., Bioinformatics and Computational Biology. "The poor prognosis of glioblastoma relates to the near universal recurrence of tumors despite robust treatment including surgery, radiotherapy and chemotherapy," said Hu. "Our study shows the potential for a new therapeutic strategy based on targeting the mechanisms allowing glioma to re-grow aggressively in the brain." Hu and his colleagues developed a glioblastoma model to locate glioma stem cells, which, like all stem calls, have the ability to become other cell types. The researchers further found that the gene, WNT5A, when activated, allowed glioma stem cells to transition, leading to invasive tumor growth. "We uncovered a process by which glioma stem cells mediated by the WNT5A gene become endothelial-like cells," said Hu. "These new cells known as GdECs, recruit existing endothelial cells to form a niche supporting the growth of invasive glioma cells away from the primary tumor, and often leading to satellite "lesions" and disease recurrence." Clinical data revealed higher WNT5A and GdECs expression in these satellite lesions and recurrent tumors than was observed in the primary tumors, affirming the tie between WNT5A-mediated stem cell differentiation and glioma cell spread throughout the brain, and contributing to the cancer's lethalness. The study established WNT5A as a key factor in glioma stem cells transitioning to GdECs. The team believes this opens up the possibility for a new therapeutic strategy for patients with glioblastoma. Recent clinical data show the FDA-approved drug, bevacizumab, did not benefit patients as a first line treatment of recurrent glioblastoma by targeting vascular endothelial growth factors (VEGF). With this new information, the study team proposes an additional therapeutic approach targeting WNT5A and VEGF signaling pathways for recurrent glioblastoma. "Our preliminary data show that bevacizumab may increase WNT5A-mediated GdECs differentiation and recruitment of existing endothelial cells resulting in no proven benefit to patients with glioblastoma" said Hu. "This new strategy should improve the outcome of brain cancer patients undergoing VEGF therapy, by limiting new tumor growth and invasion, and disease recurrence," said Hu. MD Anderson study team members included Y. Alan Wang, Ph.D., Sujun Hua, Ph.D., Charles-Etienne Sauvé, Derrick Ong, Ph.D., Zheng Lan, Ph.D., Yan Wing Ho, Ph.D., Marta Monasterio, Ph.D., Xin Lu, Ph.D., Pingna Deng, Guocan Wang, Ph.D., Wen-Ting Liao, Ph.D., Denise Spring, Ph.D., Jian Hu, Ph.D., and Ronald DePinho, M.D., all of Cancer Biology; Roeland Verhaak, Ph.D., Bioinformatics and Computational Biology; Jianhua Zhang, Ph.D., and Lynda Chin, M.D., Genomic Medicine; Yi Zong, Ph.D., Epigenetics and Molecular Carcinogenesis; Zhi Tan, Experimental Therapeutics; Lynda Corley and Gregory Fuller, M.D., Ph.D., Pathology; and Erik Sulman, M.D., Ph.D., Radiation Oncology. Other participating institutions included Dana-Farber Cancer Institute, Boston; Nanjing Medical University, Nanjing, China; Guangdong 999 Brain Hospital, Guangzhou, China; the Fondazione IRCCS Istituto Neurologico C. Besta, Milan; and the University of California, San Francisco. The study was funded by National Institutes of Health (P50 CA097257, 2P50CA127001, 5P01CA095616, and P30CA16672).


News Article | November 4, 2016
Site: www.biosciencetechnology.com

Scientists have measured the catastrophic genetic damage caused by smoking in different organs of the body and identified several different mechanisms by which tobacco smoking causes mutations in DNA. Researchers at the Wellcome Trust Sanger Institute, the Los Alamos National Laboratory and their collaborators found smokers accumulated an average of 150 extra mutations in every lung cell for each year of smoking one packet of cigarettes a day. Reported in the Journal Science, the study provides a direct link between the number of cigarettes smoked in a lifetime and the number of mutations in the tumour DNA. The highest mutation rates were seen in the lung cancers but tumours in other parts of the body also contained these smoking-associated mutations, explaining how smoking causes many types of human cancer. Tobacco smoking claims the lives of at least six million people every year and, if current trends continue, the World Health Organization predicts more than 1 billion tobacco-related deaths in this century. Smoking has been epidemiologically associated with at least 17 types of human cancer, but until now no-one has seen the mechanisms by which smoking causes many of these cancer types. Cancer is caused by mutations in the DNA of a cell. In the first comprehensive analysis of the DNA of cancers linked to smoking, researchers studied over 5,000 tumours, comparing cancers from smokers with cancers from people who had never smoked. They found particular molecular fingerprints of DNA damage - called mutational signatures - in the smokers' DNA, and counted how many of these particular mutations were found in the different tumours. The authors found that, on average, smoking a pack of cigarettes a day led to 150 mutations in each lung cell every year. These mutations represent individual potential start points for a cascade of genetic damage that can eventually lead to cancer. The numbers of mutations within any cancer cell will vary between individuals, but this study shows the additional mutational load caused by tobacco. Dr Ludmil Alexandrov, first author from Los Alamos National Laboratory, said: "Before now, we had a large body of epidemiological evidence linking smoking with cancer, but now we can actually observe and quantify the molecular changes in the DNA due to cigarette smoking. With this study, we have found that people who smoke a pack a day develop an average of 150 extra mutations in their lungs every year, which explains why smokers have such a higher risk of developing lung cancer." Other organs were also affected, with the study showing that a pack a day led to an estimated average 97 mutations in each cell in the larynx, 39 mutations for the pharynx, 23 mutations for mouth, 18 mutations for bladder, and 6 mutations in every cell of the liver each year. Until now, it has not been fully understood how smoking increases the risk of developing cancer in parts of the body that don't come into direct contact with smoke. However, the study revealed different mechanisms by which tobacco smoking causes these mutations, depending on the area of the body affected. Prof David Phillips, an author on the paper and Professor of Environmental Carcinogenesis at King's College London, said: "The results are a mixture of the expected and unexpected, and reveal a picture of direct and indirect effects. Mutations caused by direct DNA damage from carcinogens in tobacco were seen mainly in organs that come into direct contact with inhaled smoke. In contrast, other cells of the body suffered only indirect damage, as tobacco smoking seems to affect key mechanisms in these cells that in turn mutate DNA." The study revealed at least five distinct processes of DNA damage due to cigarette smoking. The most widespread of these is a mutational signature already found in all cancers. In this case, tobacco smoking seems to accelerate the speed of a cellular clock that mutates DNA prematurely. Professor Sir Mike Stratton, joint lead author from the Wellcome Trust Sanger Institute, said: "The genome of every cancer provides a kind of "archaeological record", written in the DNA code itself, of the exposures that caused the mutations that lead to the cancer. Our research indicates that the way tobacco smoking causes cancer is more complex than we thought. Indeed, we do not fully understand the underlying causes of many types of cancer and there are other known causes, such as obesity, about which we understand little of the underlying mechanism. This study of smoking tells us that looking in the DNA of cancers can provide provocative new clues to how cancers develop and thus, potentially, how they can be prevented."


News Article | November 4, 2016
Site: www.sciencedaily.com

Scientists have measured the catastrophic genetic damage caused by smoking in different organs of the body and identified several different mechanisms by which tobacco smoking causes mutations in DNA. Researchers at the Wellcome Trust Sanger Institute, the Los Alamos National Laboratory and their collaborators found smokers accumulated an average of 150 extra mutations in every lung cell for each year of smoking one packet of cigarettes a day. Reported in the Journal Science, the study provides a direct link between the number of cigarettes smoked in a lifetime and the number of mutations in the tumour DNA. The highest mutation rates were seen in the lung cancers but tumours in other parts of the body also contained these smoking-associated mutations, explaining how smoking causes many types of human cancer. Tobacco smoking claims the lives of at least six million people every year and, if current trends continue, the World Health Organization predicts more than 1 billion tobacco-related deaths in this century. Smoking has been epidemiologically associated with at least 17 types of human cancer, but until now no-one has seen the mechanisms by which smoking causes many of these cancer types. Cancer is caused by mutations in the DNA of a cell. In the first comprehensive analysis of the DNA of cancers linked to smoking, researchers studied over 5,000 tumours, comparing cancers from smokers with cancers from people who had never smoked. They found particular molecular fingerprints of DNA damage -- called mutational signatures -- in the smokers' DNA, and counted how many of these particular mutations were found in the different tumours. The authors found that, on average, smoking a pack of cigarettes a day led to 150 mutations in each lung cell every year. These mutations represent individual potential start points for a cascade of genetic damage that can eventually lead to cancer. The numbers of mutations within any cancer cell will vary between individuals, but this study shows the additional mutational load caused by tobacco. Dr Ludmil Alexandrov, first author from Los Alamos National Laboratory, said: "Before now, we had a large body of epidemiological evidence linking smoking with cancer, but now we can actually observe and quantify the molecular changes in the DNA due to cigarette smoking. With this study, we have found that people who smoke a pack a day develop an average of 150 extra mutations in their lungs every year, which explains why smokers have such a higher risk of developing lung cancer." Other organs were also affected, with the study showing that a pack a day led to an estimated average 97 mutations in each cell in the larynx, 39 mutations for the pharynx, 23 mutations for mouth, 18 mutations for bladder, and 6 mutations in every cell of the liver each year. Until now, it has not been fully understood how smoking increases the risk of developing cancer in parts of the body that don't come into direct contact with smoke. However, the study revealed different mechanisms by which tobacco smoking causes these mutations, depending on the area of the body affected. Prof David Phillips, an author on the paper and Professor of Environmental Carcinogenesis at King's College London, said: "The results are a mixture of the expected and unexpected, and reveal a picture of direct and indirect effects. Mutations caused by direct DNA damage from carcinogens in tobacco were seen mainly in organs that come into direct contact with inhaled smoke. In contrast, other cells of the body suffered only indirect damage, as tobacco smoking seems to affect key mechanisms in these cells that in turn mutate DNA." The study revealed at least five distinct processes of DNA damage due to cigarette smoking. The most widespread of these is a mutational signature already found in all cancers. In this case, tobacco smoking seems to accelerate the speed of a cellular clock that mutates DNA prematurely. Professor Sir Mike Stratton, joint lead author from the Wellcome Trust Sanger Institute, said: "The genome of every cancer provides a kind of "archaeological record," written in the DNA code itself, of the exposures that caused the mutations that lead to the cancer. Our research indicates that the way tobacco smoking causes cancer is more complex than we thought. Indeed, we do not fully understand the underlying causes of many types of cancer and there are other known causes, such as obesity, about which we understand little of the underlying mechanism. This study of smoking tells us that looking in the DNA of cancers can provide provocative new clues to how cancers develop and thus, potentially, how they can be prevented."


News Article | November 14, 2016
Site: www.eurekalert.org

Astronauts survive in space by wearing high-tech space suits. But how do brain cancer cells thrive when they migrate to inhospitable sites within the brain? A study at The University of Texas MD Anderson Cancer Center believes their survival may be due to deficiency of a tumor suppressor gene called quaking (QKI), a potential new target for therapies. Findings from the study, led by Jian Hu, Ph.D., assistant professor of the Department of Cancer Biology, were published in the Nov. 14 online issue of Nature Genetics. "Cancer stem cells require 'niches' to remain viable but it is unclear how they survive in an environment outside of these niches both within the same tissues or during invasion to other organs," said Hu. "We discovered that QKI is a major regulator of these cancer stem cells in glioblastoma, the deadliest type of brain tumor." "Evidence is emerging that some brain cancer cells called glioma stem cells possess an inexhaustible ability to self-renew and produce tumors that resemble the features of original tumors," said Hu. Self-renewal is a unique feature of all stem cells that creates identical "daughter" stem cells. To maintain this ability, they must be in a suitable environment providing them proper cellular cues. Hu's team knew that glioma stem cells thrived when they reside in niches, such as structures called subventricular zone, due to their ability to self-renew. "However, left unanswered is how glioma stem cells still manage to maintain this 'stemness' when they invade and migrate from their niches to other areas where optimal niches are less likely to be available," said Hu. The research team believed glioma stem cells must acquire the ability for stemness maintenance independent of their niches during invasion and migration. Using a mouse model, they studied deletion of major suppressing genes including QKI to see what correlation might exist. "Our previous studies showed that QKI is one of the tumor suppressor genes that can potentially regulate cancer stem cells and we confirmed this in our latest investigation," said Hu. QKI impacted a vital cellular activity called endocytosis, responsible for degrading the cell receptors that are essential for maintaining stem cell self-renewal. Loss of QKI can greatly enrich the level of these receptors and consequently enhance the self-renewal capacity even when glioma stem cells are not in the niches. Just as a space suit protects the astronaut from the dangers of space, a deficiency of QKI makes the new environment safe for the transported cancer stem cell. "This study may lead to cancer therapeutic opportunities by targeting the mechanisms involved in maintaining cancer stem cells," said Hu. "Although loss of QKI allows glioma stem cells to thrive, it also renders certain vulnerabilities to the cancer cells. We hope to design new therapies to target these." MD Anderson study participants included Takashi Shingu, Ph.D., Liang Yuan, Ph.D., Xin Zhou, Ph.D., Congxin Dai, Ph.D., and Baoli Hu, Ph.D., all of Cancer Biology; Siyuan Zheng, Ph.D., and Qianghu Wang, Ph.D., Genomic Medicine; Yiwen Chen, Ph.D., and Roeland Verhaak, Ph.D., Bioinformatics and Computational Biology; Yi Zhong, Ph.D., Epigenetics and Molecular Carcinogenesis; James Horner, Institute for Applied Cancer Sciences; Brandon Liebelt, M.D., Amy Heimberger, M.D., and Qing Chang, M.D., Ph.D., Neurosurgery; and Gregory Fuller, M.D., Ph.D., Pathology. The study was funded by The National Cancer Institute (2P50CA127001) and the National Institutes of Health (R00 CA172700 and CA120813).


News Article | November 3, 2016
Site: www.eurekalert.org

Scientists have measured the catastrophic genetic damage caused by smoking in different organs of the body and identified several different mechanisms by which tobacco smoking causes mutations in DNA. Researchers at the Wellcome Trust Sanger Institute, the Los Alamos National Laboratory and their collaborators found smokers accumulated an average of 150 extra mutations in every lung cell for each year of smoking one packet of cigarettes a day. Reported in the Journal Science, the study provides a direct link between the number of cigarettes smoked in a lifetime and the number of mutations in the tumour DNA. The highest mutation rates were seen in the lung cancers but tumours in other parts of the body also contained these smoking-associated mutations, explaining how smoking causes many types of human cancer. Tobacco smoking claims the lives of at least six million people every year and, if current trends continue, the World Health Organization predicts more than 1 billion tobacco-related deaths in this century. Smoking has been epidemiologically associated with at least 17 types of human cancer, but until now no-one has seen the mechanisms by which smoking causes many of these cancer types. Cancer is caused by mutations in the DNA of a cell. In the first comprehensive analysis of the DNA of cancers linked to smoking, researchers studied over 5,000 tumours, comparing cancers from smokers with cancers from people who had never smoked. They found particular molecular fingerprints of DNA damage - called mutational signatures - in the smokers' DNA, and counted how many of these particular mutations were found in the different tumours. The authors found that, on average, smoking a pack of cigarettes a day led to 150 mutations in each lung cell every year. These mutations represent individual potential start points for a cascade of genetic damage that can eventually lead to cancer. The numbers of mutations within any cancer cell will vary between individuals, but this study shows the additional mutational load caused by tobacco. Dr Ludmil Alexandrov, first author from Los Alamos National Laboratory, said: "Before now, we had a large body of epidemiological evidence linking smoking with cancer, but now we can actually observe and quantify the molecular changes in the DNA due to cigarette smoking. With this study, we have found that people who smoke a pack a day develop an average of 150 extra mutations in their lungs every year, which explains why smokers have such a higher risk of developing lung cancer." Other organs were also affected, with the study showing that a pack a day led to an estimated average 97 mutations in each cell in the larynx, 39 mutations for the pharynx, 23 mutations for mouth, 18 mutations for bladder, and 6 mutations in every cell of the liver each year. Until now, it has not been fully understood how smoking increases the risk of developing cancer in parts of the body that don't come into direct contact with smoke. However, the study revealed different mechanisms by which tobacco smoking causes these mutations, depending on the area of the body affected. Prof David Phillips, an author on the paper and Professor of Environmental Carcinogenesis at King's College London, said: "The results are a mixture of the expected and unexpected, and reveal a picture of direct and indirect effects. Mutations caused by direct DNA damage from carcinogens in tobacco were seen mainly in organs that come into direct contact with inhaled smoke. In contrast, other cells of the body suffered only indirect damage, as tobacco smoking seems to affect key mechanisms in these cells that in turn mutate DNA." The study revealed at least five distinct processes of DNA damage due to cigarette smoking. The most widespread of these is a mutational signature already found in all cancers. In this case, tobacco smoking seems to accelerate the speed of a cellular clock that mutates DNA prematurely. Professor Sir Mike Stratton, joint lead author from the Wellcome Trust Sanger Institute, said: "The genome of every cancer provides a kind of "archaeological record", written in the DNA code itself, of the exposures that caused the mutations that lead to the cancer. Our research indicates that the way tobacco smoking causes cancer is more complex than we thought. Indeed, we do not fully understand the underlying causes of many types of cancer and there are other known causes, such as obesity, about which we understand little of the underlying mechanism. This study of smoking tells us that looking in the DNA of cancers can provide provocative new clues to how cancers develop and thus, potentially, how they can be prevented." Los Alamos National Laboratory, a multidisciplinary research institution engaged in strategic science on behalf of national security, is operated by Los Alamos National Security, LLC, a team composed of Bechtel National, the University of California, BWXT Government Group, and URS, an AECOM company, for the Department of Energy's National Nuclear Security Administration. Los Alamos enhances national security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction and solving problems related to energy, environment, infrastructure, health and global security concerns. http://www. King's College London is one of the top 25 universities in the world (2016/17 QS World University Rankings) and among the oldest in England. King's has more than 27,600 students (of whom nearly 10,500 are graduate students) from some 150 countries worldwide, and some 6,800 staff. King's has an outstanding reputation for world-class teaching and cutting-edge research. In the 2014 Research Excellence Framework (REF) King's was ranked 6th nationally in the 'power' ranking, which takes into account both the quality and quantity of research activity, and 7th for quality according to Times Higher Education rankings. Eighty-four per cent of research at King's was deemed 'world-leading' or 'internationally excellent' (3* and 4*). The university is in the top seven UK universities for research earnings and has an overall annual income of more than £684 million. http://www. The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www. Wellcome exists to improve health for everyone by helping great ideas to thrive. We're a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate. http://www.


News Article | November 3, 2016
Site: www.eurekalert.org

LOS ALAMOS, N.M., November 4, 2016 -- A broad computational study of cancer genome sequences identifies telltale mutational signatures associated with smoking tobacco and demonstrates, for the first time, that smoking increases cancer risk by causing somatic mutations in tissues directly and indirectly exposed to tobacco smoke. The international study by Los Alamos National Laboratory with the UK's Wellcome Trust Sanger Institute and other collaborators was published in the November 4 issue of Science. "This study offers fresh insights into how tobacco smoke causes cancer," said Dr. Ludmil Alexandrov, Oppenheimer Fellow at Los Alamos National Laboratory and co-lead author of the study. "Our analysis demonstrates that tobacco smoking causes mutations that lead to cancer by multiple distinct mechanisms. Tobacco smoking damages DNA in organs directly exposed to smoke as well as speeds up a mutational cellular clock in organs that are both directly and indirectly exposed to smoke." Tobacco smoke is a complex witch's brew containing more than 7,000 chemicals including over 70 known to cause cancer (carcinogens). Previous large-scale epidemiological studies have associated tobacco smoking with increased risk for 17 different types of cancer, including cancer in tissue not directly exposed to smoke. However, the mechanisms by which tobacco smoking causes cancer have previously remained elusive. This study demonstrates that smoking increases cancer risk by causing somatic mutations that both directly damage DNA and increase the speed of an endogenous molecular clock. "This research brings together Big Data generated by international cancer consortia and the supercomputing and machine-learning capabilities of Los Alamos to address one of the leading public health issues of our time," said Laboratory Director Charlie McMillan. "Alexandrov's work leverages pattern-recognition software in genomic screening and represents a creative breakthrough in cancer research." The study, "Mutational signatures associated with tobacco smoking in human cancer," focused on identifying the mutation signatures and methylation changes in 5,243 genome sequences of smoking-related cancers by comparing the cancers of smokers to those of non-smokers. Professor Sir Mike Stratton, joint lead author from the Wellcome Trust Sanger Institute, Cambridge, UK, said: "The genome of every cancer provides a kind of 'archaeological record,' written in the DNA code itself, of the exposures that caused the mutations that lead to the cancer. Our research indicates that the way tobacco smoking causes cancer is more complex than we thought. Indeed, we do not fully understand the underlying causes of many types of cancer and there are other known causes, such as obesity, about which we understand little of the underlying mechanism. This study of smoking tells us that looking in the DNA of cancers can provide provocative new clues to how cancers develop and thus, potentially, how they can be prevented." All mutations--harmless or cancerous--are due to the activity of endogenous or exogenous mutation processes. Each process leaves a signature of scrambled DNA code on the base pairs of that cell's genome. The four base pairs are made up of molecular units identified by the letters A, T, G, and C. The new study found more than 20 mutational signatures across the 17 cancer types associated with tobacco smoking. However, only five of these signatures were elevated in cancers from smokers. Some cancer types had only a single mutational signature elevated in smokers, while others had multiple. One signature, called signature 4, can be traced to DNA being damaged by direct exposure to tobacco smoke. "Signature 4 is likely the direct mutational consequence of misreplication of DNA damage induced by tobacco carcinogens," particularly benzo[a]pryrene, according to the study. Signature 5, found by previous Los Alamos research to occur in all cells and to trigger mutations with clock-like regularity, correlated with increased mutations in smokers versus non-smokers. Alexandrov explains that smoking accelerates the clock function mostly likely by altering the molecular machinery underlying this signature. Other signatures reinforce the theory that smoking increases the risk of several cancer types by raising the overall number of mutations, even in tissue not directly exposed to smoke. The authors note that for some of the mutational signatures, the underlying mechanisms are still unclear. Alexandrov modeled the cancer mutational processes as a blind-source-separation problem to distinguish coherent signals from a noisy background, a methodology used in other areas of the Laboratory's research related to its nuclear-security mission. The project drew on the Laboratory's high-performance computing resources and expertise, as well as expertise in numerical optimization problems. Alexandrov is the winner of the 2016 Carcinogenesis Young Investigator Award from the journal Carcinogenesis: Integrative Cancer Research, which recognizes a recent significant contribution to carcinogenesis research by an investigator under the age of 40. In 2014, he was recognized by Forbes as one of the "30 brightest stars under the age of 30" in the field of science and healthcare. In 2015, he was awarded the Science magazine and SciLifeLab Prize for Young Scientists in genomics and proteomics and a Harold M. Weintraub Award for outstanding achievement during graduate studies in the biological sciences. He is a program member of the University of New Mexico Cancer Center. Researchers representing 16 institutions in the United States, Europe, and Asia worked on the study published by Science. More information, including a copy of the paper, "Mutational signatures associated with tobacco smoking in human cancer," can be found online at the Science press package at http://www. . A brief video summarizing the research is available on YouTube: https:/ . Los Alamos National Laboratory, a multidisciplinary research institution engaged in strategic science on behalf of national security, is operated by Los Alamos National Security, LLC, a team composed of Bechtel National, the University of California, BWXT Government Group, and URS, an AECOM company, for the Department of Energy's National Nuclear Security Administration. Los Alamos enhances national security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction and solving problems related to energy, environment, infrastructure, health and global security concerns. The Wellcome Trust Sanger Institute is one of the world's leading genome centers. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programs and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www.


News Article | March 1, 2017
Site: www.eurekalert.org

HOUSTON ? Anyone who uses an employee badge to enter a building may understand how a protein called ENL opens new possibilities for treating acute myeloid leukemia (AML), a fast-growing cancer of bone marrow and blood cells and the second most common type of leukemia in children and adults. Findings from a study at The University of Texas MD Anderson Cancer Center revealed the leukemia-boosting abilities of ENL, which contains a protein component called YEATS that "reads" histone proteins. Histone proteins make up chromatin, large clusters of DNA- and RNA-containing molecules comprising our body's chromosomes. Just as a scanner "reads" data on an identification badge, ENL recognizes a type of histone modification known as acetylation. Research results, which build upon a previous MD Anderson study of histone-reading proteins, are published in the March 1 online issue of Nature. The findings indicated treatment against ENL with a class of experimental drugs called bromodomain and extra-terminal (BET) inhibitors may be effective for treating AML. "Our study showed that ENL is required for disease maintenance in AML," said Xiaobing Shi, Ph.D., associate professor of Epigenetics and Molecular Carcinogenesis. "Depletion of ENL led to anti-leukemic effects, suppressing growth both in vivo and in vitro. Notably, disrupting ENL further sensitized leukemia cells to BET inhibitors." Histone modifications like acetylation serve as docking sites for reader proteins which recognize specific modifications, influencing downstream biological outcomes. While many such reader proteins have been identified for histone modifications called methylation, few are known to recognize histone acetylation. Shi's team employed CRISPR, a gene-editing tool, to deplete ENL and suppress cancer gene expression, which was crucial given that cancer cells often co-opt chromatin regulatory pathways. "Targeting epigenetic readers represents a class of anti-cancer therapy that we believe holds clinical promise," said Hong Wen, Ph.D., research assistant professor of Epigenetics and Molecular Carcinogenesis and co-first author of the paper. "Our study revealed ENL as a chromatin reader that regulates oncogenic programs, thus establishing ENL as a potential drug target for AML." MD Anderson study team members included Xiaolu Wang of the Department of Epigenetics and Molecular Carcinogenesis. Other participating institutions included The Rockefeller University, New York; Memorial Sloan Kettering Cancer Center, New York; Dana-Farber Cancer Institute, Boston; Tsinghua University, Beijing; Baylor College of Medicine, Houston; Icahn School of Medicine at Mount Sinai, New York; and Harvard Medical School; Boston. The study was funded by the National Institutes of Health (P30CA016672, RO1CA204639-01, CA66996, CA140575, 1R01CA204020, R01HG007538 and R01CA193466), the Cancer Prevention Research Institute of Texas (RP160237 and RP170285), the Leukemia and Lymphoma Society (LLS-SCOR 7006-13), the Robert A. Welch Foundation (G1719), the Major State Basic Research Development Program in China (2016FA0500700 and 2015CB910503), and the Tsinghua University Initiative Research program.

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