Amy Paller, MD is an Attending Physician of Dermatology and Walter J. Hamlin Professor and Chair of Dermatology, Professor of Pediatrics, in Northwestern University Feinberg School of Medicine.
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.
bMicrobiology, University of Washington School of Medicine, Seattle, WA 98195;
cMediCC! Medical Communications Consultants, Chapel Hill, NC 27517; and
dDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
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.
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.
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);
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.
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.
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
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.
