Integrated Genomic Characterization of Endometrial Carcinoma

The Cancer Genome Atlas (TCGA) is a project to catalogue genetic mutations responsible for cancer, using genome analysis techniques started in 2005. TCGA represents an effort in the War on Cancer that is applying recently developed high-throughput genome analysis techniques and is seeking to improve our ability to diagnose, treat, and prevent cancer through a better understanding of the molecular basis of this disease. In 2006 the National Cancer Institute and the National Human Genome Research Institute selected people and laboratories that will participate in this project. The goal of the project was to provide systematic, comprehensive genomic characterization and sequence analysis of three types of human cancers: glioblastoma multiforme, lung, and ovarian cancer. The project is unique in terms of the size of the patient cohort interrogated (scheduled are 500 patient samples, far more than most genomics studies), and the number of different techniques used to analyze the patient samples. Techniques that are being used include gene expression profiling, copy number variation profiling, SNP genotyping, genome wide DNA methylation profiling, microRNA profiling, and exon sequencing of at least 1,200 genes. Recently the group organizing the TCGA announced that they would sequence the entire genomes of some tumors and at least 6,000 candidate genes and microRNA sequences. This targeted sequencing is actively being performed by all three sequencing centers using hybrid-capture technology. A gene list is available on the TCGA website. In phase II, TCGA will perform whole exon sequencing on 80% of the cases and whole genome sequencing on 80% of the cases used in the project. TCGA has expanded in 2009 from a pilot to a large scale project. Over the next 5 years TCGA will provide genomic characterization and sequence analysis on 20-25 different tumor types. In FY 2010 a number of new centers have been funded to characterize these new tumor types. There are Genome Characterization Centers (GCCs) and Genome Data Analysis Centers (GDACs) funded to move this project into the next phase. The fact that the RFA for the expanded phase of TCGA included the specific funding of these analysis cores reflects the growing need for dedicated funding to bioinformatics in these large scale programs.

Science of Impossible ???

PNAS paper investigate hot topic

Misconduct accounts for the majority of retracted scientific publications

1. Ferric C. Fang^a,^b,¹, 
2. R. Grant Steen^c,¹, and 
3. Arturo Casadevall^d,¹,²

+Author Affiliations

1. Departments of ^aLaboratory Medicine and
2. ^bMicrobiology, University of Washington School of Medicine, Seattle, WA 98195;
3. ^cMediCC! Medical Communications Consultants, Chapel Hill, NC 27517; and
4. ^dDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461

1. Edited by Thomas Shenk, Princeton University, Princeton, NJ, and approved September 6, 2012 (received for review July 18, 2012)

Abstract

A detailed review of all 2,047 biomedical and life-science research articles indexed by PubMed as retracted on May 3, 2012 revealed that only 21.3% of retractions were attributable to error. In contrast, 67.4% of retractions were attributable to misconduct, including fraud or suspected fraud (43.4%), duplicate publication (14.2%), and plagiarism (9.8%). Incomplete, uninformative or misleading retraction announcements have led to a previous underestimation of the role of fraud in the ongoing retraction epidemic. The percentage of scientific articles retracted because of fraud has increased ∼10-fold since 1975. Retractions exhibit distinctive temporal and geographic patterns that may reveal underlying causes.

Public Concern?

Controversial paper that revels link between "Genetically modified maize", toxicity and cancer published...

Food and Chemical Toxicology

Available online 19 September 2012

In Press, Corrected Proof — Note to users

Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize

• Gilles-Eric Séralini^a, , , 
• Emilie Clair^a, 
• Robin Mesnage^a, 
• Steeve Gress^a, 
• Nicolas Defarge^a,
• Manuela Malatesta^b, 
• Didier Hennequin^c, 
• Joël Spiroux de Vendômois^a

• ^a University of Caen, Institute of Biology, CRIIGEN and Risk Pole, MRSH-CNRS, EA 2608, Esplanade de la Paix, Caen Cedex 14032, France
• ^b University of Verona, Department of Neurological, Neuropsychological, Morphological and Motor Sciences, Verona 37134, Italy
• ^c University of Caen, UR ABTE, EA 4651, Bd Maréchal Juin, Caen Cedex 14032, France

• http://dx.doi.org/10.1016/j.fct.2012.08.005, How to Cite or Link Using DOI

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Abstract

The health effects of a Roundup-tolerant genetically modified maize (from 11% in the diet), cultivated with or without Roundup, and Roundup alone (from 0.1 ppb in water), were studied 2 years in rats. In females, all treated groups died 2–3 times more than controls, and more rapidly. This difference was visible in 3 male groups fed GMOs. All results were hormone and sex dependent, and the pathological profiles were comparable. Females developed large mammary tumors almost always more often than and before controls, the pituitary was the second most disabled organ; the sex hormonal balance was modified by GMO and Roundup treatments. In treated males, liver congestions and necrosis were 2.5–5.5 times higher. This pathology was confirmed by optic and transmission electron microscopy. Marked and severe kidney nephropathies were also generally 1.3–2.3 greater. Males presented 4 times more large palpable tumors than controls which occurred up to 600 days earlier. Biochemistry data confirmed very significant kidney chronic deficiencies; for all treatments and both sexes, 76% of the altered parameters were kidney related. These results can be explained by the non linear endocrine-disrupting effects of Roundup, but also by the overexpression of the transgene in the GMO and its metabolic consequences.

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Highlights

► A Roundup-tolerant maize and Roundup provoked chronic hormone and sex dependent pathologies. ► Female mortality was 2–3 times increased mostly due to large mammary tumors and disabled pituitary. ► Males had liver congestions, necrosis, severe kidney nephropathies and large palpable tumors. ► This may be due to an endocrine disruption linked to Roundup and a new metabolism due to the transgene. ► GMOs and formulated pesticides must be evaluated by long term studies to measure toxic effects..

Abbreviations

• GM, genetically modified; 
• R, Roundup; 
• MRL, maximal residual levels; 
• GMO, genetically modified organism; 
• OECD, Organization for Economic Co-operation and Development; 
• GT, glutamyl-transferase; 
• PCA, principal component analysis; 
• PLS, partial least-squares; 
• OPLS, orthogonal partial least-squares; 
• NIPALS, Nonlinear Iterative Partial Least Squares; 
• OPLS-DA, Orthogonal Partial Least Squares Discriminant Analysis; 
• G, glycogen; 
• L, lipid droplet; 
• N, nucleus; 
• R, rough endoplasmic reticulum (on microscopy pictures only); 
• U, urinary; 
• UEx, excreted in urine during 24 h; 
• APPT, Activated Partial Thromboplastin Time; 
• MCV, Mean Corpuscular Volume; 
• PT, Prothrombine Time;
• RBC, Red Blood Cells; 
• ALT, alanine aminotransferase; 
• MCHC, Mean Corpuscular Hemoglobin Concentration; 
• A/G, Albumin/Globulin ratio; 
• WBC, White Blood Cells; 
• AST, aspartate aminotransferase

Keywords

• GMO; 
• Roundup; 
• NK603; 
• Rat; 
• Glyphosate-based herbicides; 
• Endocrine disrupting effects

New Step in Breast Cancer Research

The Cancer Genome Atlas Network publish online new masterpiece paper

Comprehensive molecular portraits of human breast tumours

• The Cancer Genome Atlas Network

• Affiliations
• Contributions

Nature

 

(2012)

 

doi:10.1038/nature11412

Received

 

22 March 2012 

Accepted

 

11 July 2012 

Published online

 

23 September 2012

Abstract

• Abstract
• Introduction
 
• Samples and clinical data
 
• Significantly mutated genes in breast cancer
• Mutations and mRNA-expression subtype associations
 
• Gene expression analyses (mRNA and miRNA)
• DNA methylation
 
• DNA copy number
 
• Reverse phase protein arrays
 
• Multiplatform subtype discovery
• Luminal/ER⁺ summary analysis
 
• HER2-based classifications and summary analysis
• Basal-like summary analysis
 
• Concluding remarks
 
• Methods
 
• References
 
• Acknowledgements
• Author information
 
• Supplementary information

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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 inGATA3, 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.

High Priority Areas for Evidence Generation

High Priority Areas for Evidence Generation

http://www.youtube.com/watch?v=4YluAIjeI2Q&hd=1

http://caa.ucsd.edu/home/

The Cancer Puzzle

Siddhartha Mukherjee's fascination with cancer is rooted not just in how to fight it, but in where it originated. Discovering almost nothing on the subject, the cancer physician and researcher wrote "Emperor of All Maladies: A Biography of Cancer," that explores the history of the disease that causes one quarter of all American deaths.

Molecular target identification for translational medicine: the anticancer topoisomerase I inhibitors.

Dr. Pommier received his MD and PhD degrees from the University of Paris, France and has been at the NIH since 1981. Dr. Pommier is a member of the Molecular Target steering committee at the NCI. He received an NIH Merit Award for his role in elucidating the function of topoisomerase enzymes as targets for anticancer drugs and Federal Technology Transfer Awards for studies on HIV-1 integrase and DNA topoisomerase inhibitors. Dr. Pommier is a program committee member of the American Association for Cancer Research, Senior Editor for Cancer Research, and associate editor for Cancer Research, Molecular Pharmacology, Leukemia, The Journal of Experimental Therapeutics and Oncology, The International Journal of Oncology, and Drug Resistance Updates. Dr. Pommier holds several patents for inhibitors of DNA topoisomerases I and II and HIV-1 integrase inhibitors

Macroscopic Analysis of the Disease

Macroscopic Analysis of the Disease

By Julio Diaz-Perez, Juan Barajas-Gamboa

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In recent years the study of the diseases has advanced in complexity focused in molecular and laboratory studies, perhaps this valuable advances the medical exercise are guided in more of the cases by an accurate clinical examination. For the correct identification of the patterns given for each disease the clinician need a deep background in general pathology and in the identification of a correct diagnosis.

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Cancer Research Now: Molecular Imaging in Prostate Cancer

Hereditary breast cancer: genetic code unravelled

Ground-breaking UK-led research has unravelled the complete genetic code of the most common type of hereditary breast cancer for the first time.

http://onlinelibrary.wiley.com/doi/10.1002/path.4003/abstract;jsessionid=1648B0FC2F2BAD9EA28875FBBFE626A3.d02t04

Scientists from the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research (ICR) have fully sequenced the DNA of two breast cancers caused by a faulty BRCA1 gene. Surprisingly, changes in the genetic code of the two tumours looked almost entirely different from one another. This information can now help scientists identify better treatment strategies for patients with a faulty BRCA1 gene.

The study today also produced preliminary results identifying three new breast cancer genes – DAPK3, TMEM135 and GATA4. These are tumour suppressor genes which, when mutated, could be involved in causing breast cancer or driving its growth. The results are published today online in the Journal of Pathology.

Hereditary breast cancer accounts for up to 10% of all breast cancers, or around 4,500 cases in the UK each year. The most common cause is a faulty BRCA1 gene. Women with a BRCA1 mutation have around  up to 85 per cent risk of developing breast cancer during their lifetime. BRCA1 breast cancers are usually aggressive and typically do not benefit from targeted drugs such as tamoxifen and Herceptin (trastuzumab).

Study co-author, Professor Jorge Reis-Filho, from the Breakthrough Breast Cancer Research Centre at the ICR, said: “This research has big implications for how we treat hereditary breast cancer in the future. We often consider patients with a faulty BRCA gene as one group but our work shows that each tumour can look very different from each other genetically. Now we understand this, we can start to identify the best treatment strategies to save more lives of hereditary breast cancer patients.”

The scientists looked at two tumours, both caused by a faulty BRCA1 gene, with one classified as hormone receptor negative and one hormone receptor positive. They then tracked all of the genetic mutations in both of the tumours and found only one similarity in addition to the initial BRCA1 fault. All of the additional genetic alterations were different. The hormone receptor negative tumour had around twice as many mutations as the other, underlining the differences that have occurred in their DNA.

Based on the alterations found in these two cases, the scientists scanned the genome of another group of breast cancers and identified three genes that were found to be altered in several other tumours. Although these genes have not previously been linked to breast cancer, the results suggest they may drive the identification of additional subtypes of breast cancer.

Study co-author Dr Rachael Natrajan, from the Breakthrough Breast Cancer Research Centre at the ICR, said: “It is exciting to find new genes which could be involved in causing and driving breast cancer. Now these have been identified we have to do more work to find out the role that they play. Ultimately, this knowledge could help us develop new treatments that target the specific defects of each patient’s disease.”

The UK-led study also included teams from the Institut Curie in France, the University Medical Center Utrecht in the Netherlands, and The Cancer Research UK London Research Institute and the University of Nottingham in the UK.