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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 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.


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 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 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.


Kosti O.,Carcinogenesis | Byrne C.,Carcinogenesis | Meeker K.L.,Carcinogenesis | Watkins K.M.,Carcinogenesis | And 6 more authors.
Carcinogenesis | Year: 2010

Given the high incidence of breast cancer and that more than half of cases remain unexplained, the need to identify risk factors for breast cancer remains. Deficiencies in DNA repair capacity have been associated with cancer risk. The mutagen sensitivity assay (MSA), a phenotypic marker of DNA damage response and repair capacity, has been consistently shown to associate with the risk of tobacco-related cancers. Methods: In a case-control study of 164 women with breast cancer and 165 women without the disease, we investigated the association between mutagen sensitivity and risk of breast cancer using bleomycin as the mutagen. Results: High bleomycin sensitivity (>0.65 breaks per cell) was associated with an increased risk of breast cancer, with an adjusted odds ratio of 2.8 [95% confidence interval (CI) 5 1.7-4.5]. Risk increased with greater number of bleomycin-induced chromosomal breaks (Ptrend 5 0.01). The association between bleomycin sensitivity and breast cancer risk was greater for women who were black, premenopausal and ever smokers. Our data also suggest that bleomycin sensitivity may modulate the effect of tobacco smoking on breast cancer risk. Among women with hypersensitivity to bleomycin, ever smokers had a 1.6-fold increased risk of breast cancer (95% CI = 0.6-3.9, P for interaction between tobacco smoking and bleomycin sensitivity = 0.32). Conclusions: Increased bleomycin sensitivity is significantly associated with an increased risk of breast cancer in both preand postmenopausal women. Our observation that the effect of tobacco smoking on breast cancer risk may differ based on mutagen sensitivity status warrants further investigation. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.

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