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Publicaciones sobre Temas de Interés
NCI News Note:
Comprehensive list of gene variants developed for cancer cells from nine tissue types
Fuente: http://www.cancer.gov/newscenter/cancerresearchnews/2013/NCI-60CellLine
NCI scientists have developed a comprehensive list of genetic variants for each of the types of cells that comprise what is known as the NCI-60 cell line collection. This new list adds depth to the most frequently studied human tumor cell lines in cancer research, molecular pharmacology, and drug discovery. The NCI-60 cancer cell panel represents nine different types of cancer: breast, ovary, prostate, colon, lung, kidney, brain, leukemia, and melanoma. In this study, the investigators sequenced the whole exomes, or DNA coding regions, of each of NCI-60 cell lines, to define novel cancer variants and aberrant patterns of gene expression in tumor cells and to relate such patterns and variants to those that occur during the development of cancer. They also found correlations between specific variants in genes such as TP53, BRAF, ERBBs, and ATAD5 and the activity of anticancer agents such as nutlin, vemurafenib, erlotinib, and bleomycin.
As new cancer genes are identified through large-scale sequencing studies, results of this NCI-60 sequencing data will be a valuable resource because they pinpoint more than six billion connections between cell lines with mutations in specific genes and drugs that target those gene defects. This new data is now included in the NCI-60 and freely available in different formats and through multiple sources, including CellMiner and Ingenuity websites. The results of this study, led by Paul S. Meltzer, M.D., Ph.D., chief of the Genetics Branch, Center for Cancer Research, Yves Pommier, M.D., Ph.D., chief of Laboratory of Molecular Pharmacology, Center for Cancer Research, and James H. Doroshow, M.D., director of the Division of Cancer Treatment and Diagnosis, appeared online in Cancer Research, July 15, 2013.
Consulte artículo original en: Cancer Res. July 15, 2013, 73; 4372-82
The Exomes of the NCI-60 Panel: A Genomic Resource for Cancer Biology and Systems Pharmacology
Ogan D. Abaan1, Eric C. Polley3, Sean R. Davis1, Yuelin J. Zhu1, Sven Bilke1, Robert L. Walker1, Marbin Pineda1, Yevgeniy Gindin1, Yuan Jiang1, William C. Reinhold2, Susan L. Holbeck3, Richard M. Simon3, James H. Doroshow2,3, Yves Pommier2, and Paul S. Meltzer1
Authors' Affiliations: 1Genetics Branch; 2Laboratory of Molecular Pharmacology, Center for Cancer Research; and 3Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland
Corresponding Authors:
Yves Pommier, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Dr., Bethesda, MD 20982. Phone: 301-496-5944; Fax: 301-402-0752; E-mail: pommier@nih.gov; and Paul S. Meltzer, Genetics Branch, National Cancer Institute, 37 Convent Dr., Bethesda, MD 20982. Phone: 301-496-5266; Fax: 301-402-3241; E-mail: pmeltzer@mail.nih.gov. O.D. Abaan, E.C. Polley, and S.R. Davis contributed equally to this work.
Abstract
The NCI-60 cell lines are the most frequently studied human tumor cell lines in cancer research. This panel has generated the most extensive cancer pharmacology database worldwide. In addition, these cell lines have been intensely investigated, providing a unique platform for hypothesis-driven research focused on enhancing our understanding of tumor biology. Here, we report a comprehensive analysis of coding variants in the NCI-60 panel of cell lines identified by whole exome sequencing, providing a list of possible cancer specific variants for the community. Furthermore, we identify pharmacogenomic correlations between specific variants in genes such as TP53, BRAF, ERBBs, and ATAD5 and anticancer agents such as nutlin, vemurafenib, erlotinib, and bleomycin showing one of many ways the data could be used to validate and generate novel hypotheses for further investigation. As new cancer genes are identified through large-scale sequencing studies, the data presented here for the NCI-60 will be an invaluable resource for identifying cell lines with mutations in such genes for hypothesis-driven research. To enhance the utility of the data for the greater research community, the genomic variants are freely available in different formats and from multiple sources including the CellMiner and Ingenuity websites. Cancer Res; 73(14); 4372–82. ©2013 AACR.
Footnotes
• Note: Supplementary data for this article are available at Cancer Research Online http://cancerres.aacrjournals.org/
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RESEARCH REPORT
Particulate Air Pollution Contributes to Lung Cancer Risk in Huge European Study
By Dave Levitan | 9 de julio de 2013
Fuente: http://www.cancernetwork.com/lung-cancer/content/article/10165/2149846
A study including 17 cohorts with a total of more than 300,000 individuals found that ambient air pollution of various types contributes to lung cancer incidence across nine European countries.
“Ambient air pollution, specifically particulate matter with absorbed polycyclic aromatic hydrocarbons and other genotoxic chemicals, is suspected to increase the risk for lung cancer,” wrote researchers led by Ole Raaschou-Nielsen, PhD, of the Danish Cancer Society Research Center in Copenhagen, online in the Lancet. The new study, known as ESCAPE, analyzed data from a number of cohorts across Europe featuring patients with a wide range of exposure levels to pollution.
Among a total of 312,944 participants and 4,013,131 person-years at risk, there were 2,095 lung cancer cases over an average follow-up period of 12.8 years. The analysis showed a significant association between the risk of lung cancer and concentrations of particulate matter (PM) with a diameter of less than 10 µm (PM10) near where participants live; the hazard ratio (HR) was 1.22 (95% CI, 1.03–1.45) per 10 µg/m3. For smaller particles known as PM2.5, the HR was not significant, at 1.18 (95% CI, 0.96–1.46) per 5 µg/m3.
PM10 was associated with an HR for adenocarcinoma specifically of 1.51 (95% CI, 1.10–2.08), while PM2.5 yielded an HR of 1.55 (95% CI, 1.05–2.29). Furthermore, though it did not reach significance, the amount of road traffic near a residence appears to play a role in lung cancer risk: an increase of 4,000 vehicle-kilometers per day within 100 meters of the residence gave an HR for lung cancer of 1.09 (95% CI, 0.99–1.21). There was no association between cancer and nitrogen oxide concentration or traffic intensity on the nearest street.
The authors concluded that the associations seen in this study add “substantially to the weight of the epidemiological evidence.” The study does have limitations, including the combination across cohorts and the fact that “the effects of single air pollutants are difficult to disentangle in an epidemiological study because pollutants are part of complex mixtures.” Previous research, though, does suggest that particulate matter is the most important component of those mixtures to lung cancer risk.
Notably, there did not appear to be a point below which the risk associated with particulate matter pollution disappears. According to a press release, the authors said that the association persisted even at concentrations below the European Union air quality limit values. “We found no threshold below which there was no risk; the results showed a picture that ‘the more the worse, the less the better.’ ”
In an accompanying editorial in the Lancet, Takashi Yorifuji, MD, PhD, of Okayama University Graduate School of Environmental and Life Science in Japan, said that “we might have to add air pollution, even at current concentrations, to the list of causes of lung cancer and recognize that air pollution has large effects on public health, although fortunately, like tobacco smoking, it is a controllable factor.”
Consulte artículo original en:
The Lancet Oncology, Early Online Publication, 10 July 2013
http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2813%2970279-1/abstract
Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE)
Dr Ole Raaschou-Nielsen PhD a , Zorana J Andersen PhD a b, Rob Beelen PhD c, Evangelia Samoli PhD d, Massimo Stafoggia MSc e, Gudrun Weinmayr PhD f g, Prof Barbara Hoffmann MD g h, Paul Fischer MSc i, Mark J Nieuwenhuijsen PhD j, Prof Bert Brunekreef PhD c k, Wei W Xun MPH l, Prof Klea Katsouyanni PhD d, Konstantina Dimakopoulou MSc d, Johan Sommar MSc m, Prof Bertil Forsberg PhD m, Lars Modig PhD m, Anna Oudin PhD m, Bente Oftedal PhD n, Per E Schwarze PhD n, Prof Per Nafstad MD n o, Prof Ulf De Faire PhD p, Prof Nancy L Pedersen PhD q, Prof Claes-Göran Östenson PhD r, Laura Fratiglioni PhD s, Johanna Penell PhD p, Michal Korek MSc p, Prof Göran Pershagen PhD p, Kirsten T Eriksen PhD a, Mette Sørensen PhD a, Anne Tjønneland DMSc a, Thomas Ellermann PhD t, Marloes Eeftens MSc c, Prof Petra H Peeters PhD k, Kees Meliefste BSc c, Meng Wang MSc c, Bas Bueno-de-Mesquita PhD i, Prof Timothy J Key DPhil u, Kees de Hoogh PhD l, Hans Concin MD v, Gabriele Nagel PhD f v, Alice Vilier MSc w x y, Sara Grioni BSc z, Vittorio Krogh MD z, Ming-Yi Tsai PhD aa ab, Fulvio Ricceri PhD ac, Carlotta Sacerdote PhD ad, Claudia Galassi MD ad, Enrica Migliore MSc ad, Andrea Ranzi PhD ae, Giulia Cesaroni MSc e, Chiara Badaloni MSc e, Francesco Forastiere PhD e, Ibon Tamayo MSc af, Pilar Amiano MSc ag, Miren Dorronsoro MD ag, Prof Antonia Trichopoulou MD d ah, Christina Bamia PhD d, Prof Paolo Vineis MPH l †, Gerard Hoek PhD c †
Summary
Background
Ambient air pollution is suspected to cause lung cancer. We aimed to assess the association between long-term exposure to ambient air pollution and lung cancer incidence in European populations.
Methods
This prospective analysis of data obtained by the European Study of Cohorts for Air Pollution Effects used data from 17 cohort studies based in nine European countries. Baseline addresses were geocoded and we assessed air pollution by land-use regression models for particulate matter (PM) with diameter of less than 10 μm (PM10), less than 2•5 μm (PM2•5), and between 2•5 and 10 μm (PMcoarse), soot (PM2•5absorbance), nitrogen oxides, and two traffic indicators. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses.
Findings
The 312 944 cohort members contributed 4 013 131 person-years at risk. During follow-up (mean 12•8 years), 2095 incident lung cancer cases were diagnosed. The meta-analyses showed a statistically significant association between risk for lung cancer and PM10 (hazard ratio [HR] 1•22 [95% CI 1•03—1•45] per 10 μg/m3). For PM2•5 the HR was 1•18 (0•96—1•46) per 5 μg/m3. The same increments of PM10 and PM2•5 were associated with HRs for adenocarcinomas of the lung of 1•51 (1•10—2•08) and 1•55 (1•05—2•29), respectively. An increase in road traffic of 4000 vehicle-km per day within 100 m of the residence was associated with an HR for lung cancer of 1•09 (0•99—1•21). The results showed no association between lung cancer and nitrogen oxides concentration (HR 1•01 [0•95—1•07] per 20 μg/m3) or traffic intensity on the nearest street (HR 1•00 [0•97—1•04] per 5000 vehicles per day).
Interpretation
Particulate matter air pollution contributes to lung cancer incidence in Europe.
Funding
European Community's Seventh Framework Programme.
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ANNOUNCEMENT
ASCO Adds New Drug to Breast Cancer Prevention Guidelines
By Anna Azvolinsky, PhD1 | 10 de julio de 2013
Fuente: http://www.cancernetwork.com/breast-cancer/content/article/10165/2149814
The American Society of Clinical Oncology (ASCO) has published updated guidelines, “Use of Pharmacologic Interventions for Breast Cancer Risk Reduction,” for women at high risk of developing breast cancer. The guidelines are published in the Journal of Clinical Oncology.
Ball-and-stick model of exemestane (Drug information on exemestane)
The new guidelines now include exemestane (Aromasin), an aromatase inhibitor, for the prevention of breast cancer in postmenopausal women at risk for estrogen receptor (ER)-positive disease. The previous guidelines, published in 2009, emphasized that exemestane should only be used to help prevent breast cancer in a clinical trial setting.
The guidelines also updated the recommendations for both tamoxifen (Drug information on tamoxifen) and raloxifene (Drug information on raloxifene) as a prophylactic measure to prevent ER-positive breast cancer, based on studies published since 2009.
Scott M. Lippman, MD, director of the University of California San Diego Moores Cancer Center and colleagues reviewed 19 randomized, controlled studies from 2007 to 2012 for the updated guidelines, which are intended for clinicians who treat women with breast cancer (including medical and surgical oncologists, primary care physicians, gynecologists, and general practitioners). An increased risk is defined as a “projected 5-year absolute risk of breast cancer greater than or equal to 1.66% using the National Cancer Institute Breast Cancer Risk Assessment Tool or an equivalent measure.”
The chemopreventive drugs considered include the estrogen-receptor modulators tamoxifen, raloxifene, arzoxifene, and lasofoxifene; and the aromatase inhibitors exemestane and anastrozole(Drug information on anastrozole).
For women who are 35 years or older, 5 years of tamoxifen at 20 mg per day is listed as an option to reduce the risk of developing invasive, ER-positive breast cancer or for those who have lobular carcinoma in situ. Tamoxifen for 5 years is recommended for both premenopausal and postmenopausal women. However, the oral therapy is not indicated for women with a history of blood clots, stroke, or transient ischemic heart attacks. Four phase III trials—the National Surgical Adjuvant Breast and Bowel Project P-1 (NSABP-P1), the International Breast Cancer Intervention Study (IBIS-I), the Royal Marsden Tamoxifen Prevention Trial, and the Italian Randomized Tamoxifen Prevention Trial—have prospectively assessed tamoxifen for reducing the risk of breast cancer.
Raloxifene at 60 mg per day for 5 years is another option for women who are postmenopausal, but it is not indicated for women who have not yet reached menopause. Like tamoxifen, raloxifene is not indicated for women with a history of blood clots, stroke, or heart attacks. A total of three trials—Raloxifene Use for the Heart (RUTH), Multiple Outcomes of Raloxifene Evaluation (MORE), and Continuing Outcomes Relevant to Evista (CORE)—evaluated raloxifene, specifically in postmenopausal women.
At a dose of 25 mg per day, the aromatase inhibitor exemestane is now an option to reduce the risk of ER-positive breast cancer in postmenopausal women, based on results of the MAP.3 trial. Exemestane is not currently approved for prevention by the US Food and Drug Administration (FDA). Exemestane is FDA-approved for the treatment of early- or late-stage breast cancer in postmenopausal women.
The MAP.3 trial results, published in the New England Journal of Medicine, showed that women who take exemestane had a relative reduction in breast cancer incidence of 65% compared with those who took placebo (P = .002). The incidence of both invasive and noninvasive breast cancers in the exemestane arm was 0.35% compared with 0.77% in the placebo arm (P = .004).
The best risk-to-benefit profile for either tamoxifen or raloxifene, based on the published studies, is for those women with the greatest risk of breast cancer.
The guideline committee highlighted the strong evidence from phase III randomized trials with both tamoxifen and raloxifene that have demonstrated a significant reduction in breast cancer risk. However, none of the tamoxifen or raloxifene studies were powered to detect differences in breast cancer mortality, rather, incidence of breast cancer was the primary clinical endpoint.
Thus far, there have not been any results from phase III trials assessing risk reduction of breast cancer with raloxifene or aromatase inhibitors for women who are BRCA1 or BRCA2 mutation carriers. While clinical trials with tamoxifen have included BRCA mutation carriers, there have not been enough of these participants in trials to measure a statistically significant effect of the agents on this population of women.
Communication between patient and physician is key in determining the patient’s risk of breast cancer and deciding on a suitable course of prevention. As many as 2 million women may benefit from chemopreventive drugs, but the number of women, even those at the highest risk for developing breast cancer, do not commonly opt for these longer term chemopreventive measures mostly because of the side effects that come with the prophylaxis. The patient–clinician conversation also needs to include lifestyle and surgery options which were not included in these specific guidelines, as well as adverse effects and cost issues.
Consulte artículo original en:
JCO, July 8, 2013 http://jco.ascopubs.org/content/early/2013/07/03/JCO.2013.49.3122.abstract
Use of Pharmacologic Interventions for Breast Cancer Risk Reduction: American Society of Clinical Oncology Clinical Practice Guideline
Kala Visvanathan, Patricia Hurley, Elissa Bantug, Powel Brown, Nananda F. Col, Jack Cuzick, Nancy E. Davidson, Andrea DeCensi, Leslie Ford, Judy Garber, Maria Katapodi, Barnett Kramer, Monica Morrow, Barbara Parker, Carolyn Runowicz, Victor G. Vogel III, James L. Wade and Scott M. Lippman
Author Affiliations
Kala Visvanathan, Johns Hopkins Medical Institutions; Elissa Bantug, Johns Hopkins Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore; Leslie Ford and Barnett Kramer, National Cancer Institute, Bethesda, MD; Patricia Hurley, American Society of Clinical Oncology, Alexandria, VA; Powel Brown, MD Anderson Cancer Center, University of Texas, Houston, TX; Nananda F. Col, University of New England, Biddeford, ME; Jack Cuzick, Queen Mary University of London, London, United Kingdom; Nancy E. Davidson, University of Pittsburgh Cancer Institute and Medical Center Cancer Center, Pittsburgh; Victor G. Vogel III, Geisinger Medical Center Cancer Institute, Danville, PA; Andrea DeCensi, Ente Ospedaliero Ospedali Galliera, Genoa, Italy; Carol Fabian, University of Kansas Medical Center, Kansas City, KS; Judy Garber, Dana-Farber Cancer Institute, Boston, MA; Maria Katapodi, University of Michigan School of Nursing, Ann Arbor, MI; Monica Morrow, Memorial Sloan-Kettering Cancer Center, New York, NY; Barbara Parker and Scott M. Lippman, Moores Cancer Center, University of California, San Diego, San Diego, CA; Carolyn Runowicz, Herbert Wertheim College of Medicine, Florida International University, Miami, FL; and James L. Wade, Cancer Care Specialists of Central Illinois, Decatur, IL.
1. Corresponding author: American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; e-mail: guidelines@asco.org.
Abstract
Purpose To update the 2009 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction.
Methods A systematic review of randomized controlled trials and meta-analyses published from June 2007 through June 2012 was completed using MEDLINE and Cochrane Collaboration Library. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. Guideline recommendations were revised based on an Update Committee’s review of the literature.
Results Nineteen articles met the selection criteria. Six chemoprevention agents were identified: tamoxifen, raloxifene, arzoxifene, lasofoxifene, exemestane, and anastrozole.
Recommendations In women at increased risk of BC age ≥ 35 years, tamoxifen (20 mg per day for 5 years) should be discussed as an option to reduce the risk of estrogen receptor (ER) –positive BC. In postmenopausal women, raloxifene (60 mg per day for 5 years) and exemestane (25 mg per day for 5 years) should also be discussed as options for BC risk reduction. Those at increased BC risk are defined as individuals with a 5-year projected absolute risk of BC ≥ 1.66% (based on the National Cancer Institute BC Risk Assessment Tool or an equivalent measure) or women diagnosed with lobular carcinoma in situ. Use of other selective ER modulators or other aromatase inhibitors to lower BC risk is not recommended outside of a clinical trial. Health care providers are encouraged to discuss the option of chemoprevention among women at increased BC risk. The discussion should include the specific risks and benefits associated with each chemopreventive agent.
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