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Margaret R. Spitz

Bio: Margaret R. Spitz is an academic researcher from University of Texas MD Anderson Cancer Center. The author has contributed to research in topics: Lung cancer & Cancer. The author has an hindex of 91, co-authored 397 publications receiving 31397 citations. Previous affiliations of Margaret R. Spitz include University of Mississippi Medical Center & Baylor College of Medicine.
Topics: Lung cancer, Cancer, Odds ratio, Genotype, Risk factor


Papers
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Journal ArticleDOI
Li Ding1, Gad Getz2, David A. Wheeler3, Elaine R. Mardis1, Michael D. McLellan1, Kristian Cibulskis2, Carrie Sougnez2, Heidi Greulich2, Heidi Greulich4, Donna M. Muzny3, Margaret Morgan3, Lucinda Fulton1, Robert S. Fulton1, Qunyuan Zhang1, Michael C. Wendl1, Michael S. Lawrence2, David E. Larson1, Ken Chen1, David J. Dooling1, Aniko Sabo3, Alicia Hawes3, Hua Shen3, Shalini N. Jhangiani3, Lora Lewis3, Otis Hall3, Yiming Zhu3, Tittu Mathew3, Yanru Ren3, Jiqiang Yao3, Steven E. Scherer3, Kerstin Clerc3, Ginger A. Metcalf3, Brian Ng3, Aleksandar Milosavljevic3, Manuel L. Gonzalez-Garay3, John R. Osborne1, Rick Meyer1, Xiaoqi Shi1, Yuzhu Tang1, Daniel C. Koboldt1, Ling Lin1, Rachel Abbott1, Tracie L. Miner1, Craig Pohl1, Ginger A. Fewell1, Carrie A. Haipek1, Heather Schmidt1, Brian H. Dunford-Shore1, Aldi T. Kraja1, Seth D. Crosby1, Christopher S. Sawyer1, Tammi L. Vickery1, Sacha N. Sander1, Jody S. Robinson1, Wendy Winckler4, Wendy Winckler2, Jennifer Baldwin2, Lucian R. Chirieac4, Amit Dutt4, Amit Dutt2, Timothy Fennell2, Megan Hanna4, Megan Hanna2, Bruce E. Johnson4, Robert C. Onofrio2, Roman K. Thomas5, Giovanni Tonon4, Barbara A. Weir2, Barbara A. Weir4, Xiaojun Zhao2, Xiaojun Zhao4, Liuda Ziaugra2, Michael C. Zody2, Thomas J. Giordano6, Mark B. Orringer6, Jack A. Roth, Margaret R. Spitz7, Ignacio I. Wistuba, Bradley A. Ozenberger8, Peter J. Good8, Andrew C. Chang6, David G. Beer6, Mark A. Watson1, Marc Ladanyi9, Stephen R. Broderick9, Akihiko Yoshizawa9, William D. Travis9, William Pao9, Michael A. Province1, George M. Weinstock1, Harold E. Varmus9, Stacey Gabriel2, Eric S. Lander2, Richard A. Gibbs3, Matthew Meyerson4, Matthew Meyerson2, Richard K. Wilson1 
23 Oct 2008-Nature
TL;DR: Somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B are found.
Abstract: Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.

2,615 citations

Journal ArticleDOI
Barbara A. Weir1, Barbara A. Weir2, Michele S. Woo2, Gad Getz1, Sven Perner3, Sven Perner2, Li Ding4, Rameen Beroukhim2, Rameen Beroukhim1, William M. Lin2, William M. Lin1, Michael A. Province4, Aldi T. Kraja4, Laura A. Johnson2, Kinjal Shah1, Kinjal Shah2, Mitsuo Sato5, Roman K. Thomas6, Justine A. Barletta2, Ingrid B. Borecki4, Stephen R. Broderick7, Andrew C. Chang8, Derek Y. Chiang1, Derek Y. Chiang2, Lucian R. Chirieac2, Jeonghee Cho2, Yoshitaka Fujii9, Adi F. Gazdar5, Thomas J. Giordano8, Heidi Greulich1, Heidi Greulich2, Megan Hanna2, Megan Hanna1, Bruce E. Johnson2, Mark G. Kris7, Alex E. Lash7, Ling Lin4, Neal I. Lindeman2, Elaine R. Mardis4, John Douglas Mcpherson10, John D. Minna5, Margaret Morgan10, Mark Nadel2, Mark Nadel1, Mark B. Orringer8, John R. Osborne4, Brad Ozenberger11, Alex H. Ramos1, Alex H. Ramos2, James T. Robinson1, Jack A. Roth12, Valerie W. Rusch7, Hidefumi Sasaki9, Frances A. Shepherd13, Carrie Sougnez1, Margaret R. Spitz12, Ming-Sound Tsao13, David Twomey1, Roel G.W. Verhaak14, George M. Weinstock10, David A. Wheeler10, Wendy Winckler1, Wendy Winckler2, Akihiko Yoshizawa7, Soyoung Yu2, Maureen F. Zakowski7, Qunyuan Zhang4, David G. Beer8, Ignacio I. Wistuba12, Mark A. Watson4, Levi A. Garraway1, Levi A. Garraway2, Marc Ladanyi7, William D. Travis7, William Pao7, Mark A. Rubin1, Mark A. Rubin2, Stacey Gabriel1, Richard A. Gibbs10, Harold E. Varmus7, Richard K. Wilson4, Eric S. Lander1, Eric S. Lander14, Eric S. Lander2, Matthew Meyerson2, Matthew Meyerson1 
06 Dec 2007-Nature
TL;DR: A large-scale project to characterize copy-number alterations in primary lung adenocarcinomas using dense single nucleotide polymorphism arrays identifies NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung carcinomas.
Abstract: Somatic alterations in cellular DNA underlie almost all human cancers 1 . The prospect of targeted therapies 2 and the development of high-resolution, genome-wide approaches 3–8 are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection oftumours(n 5371)usingdensesinglenucleotidepolymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scalecopy-numbergainorloss,ofwhichonlyahandfulhave been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineagespecific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered. A collection of 528 snap-frozen lung adenocarcinoma resection specimens, with at least 70% estimated tumour content, was selected by a panel of thoracic pathologists (Supplementary Table 1); samples were anonymized to protect patient privacy. Tumour and normal DNAs were hybridized to Affymetrix 250K Sty single nucleotide polymorphism (SNP)arrays. Genomic copy number foreach ofover 238,000 probe sets was determined by calculating the intensity ratio between the tumour DNA and the average of a set of normal DNAs 9,10 . Segmented copy numbers for each tumour were inferred with the GLAD (gain and loss analysis of DNA) algorithm 11 and normalized to a median of two copies. Each copy number profile was then subjected to quality control, resulting in 371 high-quality samples used for further analysis, of which 242 had matched normal

1,087 citations

Journal ArticleDOI
TL;DR: If these findings can be confirmed in prospective studies, measuring levels of IGF-I and IGFBP-3 in blood may prove useful in assessing lung cancer risk.
Abstract: Background: Insulin-like growth factors (IGFs), in particular IGF-I and IGF-II, strongly stimulate the proliferation of a variety of cancer cells, including those from lung cancer. To examine the possible causal role of IGFs in lung cancer development, we compared plasma levels of IGF-I, IGF-II, and an IGF-binding protein (IGFBP-3) in patients with newly diagnosed lung cancer and in control subjects. Methods: From an ongoing hospital-based, case‐control study, we selected 204 consecutive patients with histologically confirmed, primary lung cancer and 218 control subjects who were matched to the case patients by age, sex, race, and smoking status. IGF-I, IGF-II, and IGFBP-3 plasma levels were measured by enzyme-linked immunosorbent assay and then divided into quartiles, based on their distribution in the control subjects. Associations between the IGF variables and lung cancer risk were estimated by use of odds ratios (ORs). Reported P values are two-sided. Results: IGF and IGFBP-3 levels were positively correlated (all r>.27; all P<.001). High plasma levels of IGF-I were associated with an increased risk of lung cancer (OR = 2.06; 95% confidence interval [CI] = 1.19‐3.56; P = .01), and this association was dose dependent in both univariate and multivariate analyses. Plasma IGFBP-3 showed no association with lung cancer risk unless adjusted for IGF-I level; when both of these variables were analyzed together, high plasma levels of IGFBP-3 were associated with reduced risk of lung cancer (OR = 0.48; 95% CI = 0.25‐0.92; P = .03). IGF-II was not associated with lung cancer risk. Conclusions: Plasma levels of IGF-I are higher and plasma levels of IGFBP-3 are lower in patients with lung cancer than in control subjects. If these findings can be confirmed in prospective studies, measuring levels of IGF-I and IGFBP-3 in blood may prove useful in assessing lung cancer risk. [J Natl Cancer Inst 1999;91:151‐6]

556 citations

Journal ArticleDOI
TL;DR: The PhenX Toolkit provides the research community with a core set of high-quality, well-established, low-burden measures intended for use in large-scale genomic studies and includes links to standards and resources in an effort to facilitate data harmonization to legacy data.
Abstract: The potential for genome-wide association studies to relate phenotypes to specific genetic variation is greatly increased when data can be combined or compared across multiple studies. To facilitate replication and validation across studies, RTI International (Research Triangle Park, North Carolina) and the National Human Genome Research Institute (Bethesda, Maryland) are collaborating on the consensus measures for Phenotypes and eXposures (PhenX) project. The goal of PhenX is to identify 15 high-priority, well-established, and broadly applicable measures for each of 21 research domains. PhenX measures are selected by working groups of domain experts using a consensus process that includes input from the scientific community. The selected measures are then made freely available to the scientific community via the PhenX Toolkit. Thus, the PhenX Toolkit provides the research community with a core set of high-quality, well-established, low-burden measures intended for use in large-scale genomic studies. PhenX measures will have the most impact when included at the experimental design stage. The PhenX Toolkit also includes links to standards and resources in an effort to facilitate data harmonization to legacy data. Broad acceptance and use of PhenX measures will promote cross-study comparisons to increase statistical power for identifying and replicating variants associated with complex diseases and with gene-gene and gene-environment interactions.

540 citations

Journal ArticleDOI
TL;DR: A genome-wide association study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls confirmed the most significant association was attained at 15q25.1 and identified two newly associated risk loci mapping to 6p21.33 and 5p15.33.
Abstract: We conducted a genome-wide association (GWA) study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls. The most significant association was attained at 15q25.1 (rs8042374; P = 7.75 x 10(-12)), confirming recent observations. Pooling data with two other GWA studies (5,095 cases, 5,200 controls) and with replication in an additional 2,484 cases and 3,036 controls, we identified two newly associated risk loci mapping to 6p21.33 (rs3117582, BAT3-MSH5; P(combined) = 4.97 x 10(-10)) and 5p15.33 (rs401681, CLPTM1L; P(combined) = 7.90 x 10(-9)).

533 citations


Cited by
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TL;DR: A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests.
Abstract: Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries. Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment. Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests.

23,203 citations

Journal ArticleDOI
TL;DR: This timely monograph is a distillation of knowledge of hepatitis B, C and D, based on a review of 1000 studies by a small group of scientists, and it is concluded that hepatitis D virus cannot be classified as a human carcinogen.
Abstract: Viral hepatitis in all its forms is a major public health problem throughout the world, affecting several hundreds of millions of people. Viral hepatitis is a cause of considerable morbidity and mortality both from acute infection and chronic sequelae which include, in the case of hepatitis B, C and D, chronic active hepatitis and cirrhosis. Hepatocellular carcinoma, which is one of the 10 commonest cancers worldwide, is closely associated with hepatitis B and, at least in some regions of the world, with hepatitis C virus. This timely monograph is a distillation of knowledge of hepatitis B, C and D, based on a review of 1000 studies by a small group of scientists. (It is interesting to note in passing that some 5000 papers on viral hepatitis are published annually in the world literature.) The epidemiological, clinical and experimental data on the association between infection with hepatitis B virus and primary liver cancer in humans are reviewed in a readable and succinct format. The available information on hepatitis C and progression to chronic infection is also evaluated and it is concluded (perhaps a little prematurely) that hepatitis C virus is carcinogenic. However, it is concluded that hepatitis D virus, an unusual virus with a number of similarities to certain plant viral satellites and viroids, cannot be classified as a human carcinogen. There are some minor criticisms: there are few illustrations and some complex tabulations (for example, Table 6) and no subject index. A cumulative cross index to IARC Monographs is of little value and occupies nearly 30 pages. This small volume is a useful addition to the overwhelming literature on viral hepatitis, and the presentation is similar to the excellent World Health Organisation Technical Reports series on the subject published in the past. It is strongly recommended as a readable up-to-date summary of a complex subject; and at a cost of 65 Sw.fr (approximately £34) is excellent value. A J ZUCKERMAN

11,533 citations

Journal Article
Fumio Tajima1
30 Oct 1989-Genomics
TL;DR: It is suggested that the natural selection against large insertion/deletion is so weak that a large amount of variation is maintained in a population.

11,521 citations

Journal ArticleDOI
04 Oct 2012-Nature
TL;DR: The ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity.
Abstract: We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

9,355 citations

Journal ArticleDOI
Ludmil B. Alexandrov1, Serena Nik-Zainal2, Serena Nik-Zainal3, David C. Wedge1, Samuel Aparicio4, Sam Behjati5, Sam Behjati1, Andrew V. Biankin, Graham R. Bignell1, Niccolo Bolli1, Niccolo Bolli5, Åke Borg2, Anne Lise Børresen-Dale6, Anne Lise Børresen-Dale7, Sandrine Boyault8, Birgit Burkhardt8, Adam Butler1, Carlos Caldas9, Helen Davies1, Christine Desmedt, Roland Eils5, Jorunn E. Eyfjord10, John A. Foekens11, Mel Greaves12, Fumie Hosoda13, Barbara Hutter5, Tomislav Ilicic1, Sandrine Imbeaud14, Sandrine Imbeaud15, Marcin Imielinsk14, Natalie Jäger5, David T. W. Jones16, David T. Jones1, Stian Knappskog17, Stian Knappskog11, Marcel Kool11, Sunil R. Lakhani18, Carlos López-Otín18, Sancha Martin1, Nikhil C. Munshi19, Nikhil C. Munshi20, Hiromi Nakamura13, Paul A. Northcott16, Marina Pajic21, Elli Papaemmanuil1, Angelo Paradiso22, John V. Pearson23, Xose S. Puente18, Keiran Raine1, Manasa Ramakrishna1, Andrea L. Richardson20, Andrea L. Richardson22, Julia Richter22, Philip Rosenstiel22, Matthias Schlesner5, Ton N. Schumacher24, Paul N. Span25, Jon W. Teague1, Yasushi Totoki13, Andrew Tutt24, Rafael Valdés-Mas18, Marit M. van Buuren25, Laura van ’t Veer26, Anne Vincent-Salomon27, Nicola Waddell23, Lucy R. Yates1, Icgc PedBrain24, Jessica Zucman-Rossi15, Jessica Zucman-Rossi14, P. Andrew Futreal1, Ultan McDermott1, Peter Lichter24, Matthew Meyerson20, Matthew Meyerson14, Sean M. Grimmond23, Reiner Siebert22, Elias Campo28, Tatsuhiro Shibata13, Stefan M. Pfister16, Stefan M. Pfister11, Peter J. Campbell3, Peter J. Campbell29, Peter J. Campbell30, Michael R. Stratton3, Michael R. Stratton31 
22 Aug 2013-Nature
TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
Abstract: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

7,904 citations