Agustin F Fernandez1, Yassen Assenov2, Jose Martin-Subero1, Balazs Balint1, Reiner Siebert3, Hiroaki Taniguchi4, Hiroyuki Yamamoto4, Manuel Hidalgo5, Aik-Choon Tan6, Oliver Galm7, Isidre Ferrer8, Montse Sanchez-Cespedes1, Alberto Villanueva8, Javier Carmona1, Jose V Sanchez-Mut1, Maria Berdasco1, Victor Moreno9, Gabriel Capella9, David Monk1, Esteban Ballestar1, Santiago Ropero10, Ramon Martinez11, Marta Sanchez-Carbayo12, Felipe Prosper13, Xabier Agirre13, Mario F Fraga14, Osvaldo Graña5, Luis Perez-Jurado15, Jaume Mora16, Susana Puig17, Jaime Prat18, Lina Badimon18, Annibale A Puca19, Stephen J Meltzer20, Thomas Lengauer2, John Bridgewater21, Christoph Bock22 and Manel Esteller23,24
+ Author Affiliations
1 Cancer Epigenetics and Biology Program (PEBC);
2 Max-Planck;
3 Kiel University;
4 Sapporo University;
5 Spanish National Cancer Research Centre (CNIO);
6 University of Colorado;
7 Aachen University;
8 Bellvitge Biomedical Research Institute (IDIBELL);
9 Catalan Institute of Oncology (ICO);
10 Alcala University;
11 Goettingen University;
12 Spanish Natioanl Cancer Research Centre (CNIO);
13 Navarra University;
14 Oviedo University;
15 Pompeu Fabra University;
16 Sant Joan de Deu Hospital;
17 Clinic Hospital;
18 Sant Pau Hospital;
19 Genetics S. Giovanni;
20 University of Maryland;
21 Cancer Institute London;
22 Harvard University;
23 Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
*↵ Corresponding author; email: mesteller@idibell.cat
Abstract
DNA methylation is the best characterized of the different layers that make up the epigenetic setting. Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. The recently arrived single-base-resolution technologies for DNA methylation are extremely helpful tools, but are not yet applicable and affordable for studying large groups of subjects. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1,628 human samples where we interrogated 1,505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG island hypermethylation and a loss of CpG methylation in non-CpG island promoters. Although transformed cells are those where DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the obtained DNA methylation fingerprints might be useful for translational purposes by showing that are able to identify the tumor type origin of Cancers of Unknown Primary (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps, and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases.
Received December 23, 2010.
Accepted May 23, 2011.
Copyright © 2011, Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
A DNA methylation fingerprint of 1,628 human samples
GENÉTICA
Actualidad Ultimas noticias - JANOes y agencias -
Investigadores españoles caracterizan la huella epigenética de más de 1.600 personas
JANO.es y agencias · 02 Junio 2011 09:59
El hallazgo, que se publica hoy en la revista 'Genome Research', permitirá encontrar el origen de metástasis desconocidas.
El estudio de la huella epigenética permitirá descifrar la naturaleza de los llamados 'tumores de origen desconocido'.
El Instituto de Investigación Biomédica de Bellvitge (IBIDELL), en Barcelona, ha logrado caracterizar la huella digital epigenética de 1.628 individuos, el grupo más numeroso hasta la fecha. Según Manel Esteller, director del Programa de Epigenética y Biología del Cáncer del Idibell y coordinador del estudio, el hallazgo permitirá predecir la edad y prevenir metástasis.
La investigación, que hoy se publica en la revista Genome Research, demuestra que la huella epigenética presenta modificaciones en todos los tumores. En el caso de los hereditarios, la función del ADN de los pacientes no se halla tan distorsionada.
Esteller destaca que las conclusiones del trabajo tendrán una aplicación inmediata en el campo de la oncología: la comparación de la huella epigenética de tantos sujetos permitirá descifrar la naturaleza de los llamados tumores de origen desconocido, es decir, aquellos que se diagnostican a partir de una metástasis "cuyo origen, a veces, no se puede encontrar ni siquiera después de la autopsia".
A partir de las similitudes entre la huella epigenética de algunos de estos cánceres y ciertos tumores primarios, se podrá localizar la zona del organismo donde estén alojados.
En la investigación han participado diversos investigadores del IBIDELL, vinculados tanto al Instituto Catalán de Oncología (ICO) como a la Universitat de Barcelona (UB) y el Hospital de Bellvitge.
Genome Research (2011); doi:10.1101/gr.119867.110
A DNA methylation fingerprint of 1,628 human samples
Genome Research
Genome Research
Instituto de Investigación Biomédica de Bellvitge (Idibell)
IDIBELL - Instituto de Investigación Biomèdica de Bellvitge
Actualidad Ultimas noticias - JANOes y agencias - Investigadores espanoles caracterizan la huella epigenetica de mas de 1600 personas - JANO.es - ELSEVIER
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