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ESI Special Topic: Gene Silencing
Publication Date: December 2006

Gene Silencing

ESI Special Topics: March 2007
Citing URL:

An INTERVIEW with Dr. Manel Esteller
This month, Special Topics talks with Dr. Manel Esteller about his highly cited work in gene silencing. His paper, "A gene hypermethylation profile of human cancer," (Cancer Res. 61[8]: 3225-9, 15 April 2001) ranks at #15 on our list of the top 20 papers published on gene silencing in the past decade, with 599 cites to its credit. Dr. Esteller’s record in Essential Science IndicatorsSM includes 145 papers, the bulk of which are classified in the field of Clinical Medicine, cited a total of 8,416 times to date. Dr. Esteller is the Director of the Cancer Epigenetics Laboratory at the Spanish National Cancer Center (CNIO) in Madrid, Spain.

ST:  Please tell us a little about your educational background and early research.

I am an M.D, Ph.D. I went to the School of Medicine with the firm idea of devoting myself to biomedical research, and I did an internship in Biochemistry and Molecular Biology. Later I obtained my Ph.D. in the molecular genetics of human tumors. Both degrees were obtained in the University of Barcelona, Catalonia, Spain.

“...epigenetics is a critical player in understanding how the same genotype can originate different phenotypes.”

After a short stay in United Kingdom examining the inheritance of breast cancer, I moved to the Johns Hopkins University and Medical Institutions in Baltimore, MD, where I became acquainted with the epigenetics world. In 2001 I founded the first epigenetics laboratory in Spain, where I am currently the director of the Cancer Epigenetics Laboratory at the Spanish National Cancer Centre (CNIO) in Madrid.

ST:  What first interested you in studying gene silencing?

I realized early in my career that genetics did not provide all the necessary answers to explain human disease. Genetics is often too static a process and pathologies are much more dynamic phenomena: epigenetics provides a more likely explanation for the adaptation of cells to different exposures and pharmacological treatments.

One of the key findings in the first years (1997-1999) of the methylation-associated silencing of tumor suppressor genes was the demonstration that the DNA mismatch repair gene hMLH1 (responsible for the Lynch Syndrome) was not mutated in sporadic cases, but instead was hypermethylated and this epigenetic lesion generated a DNA mutator phenotype.

ST:  Your 2001 Cancer Research paper, "A gene hypermethylation profile of human cancer," has been named a highly cited paper in our analysis. Would you please walk our readers through this paper’s origins, findings, and implications?

Until the publication of this paper, there were a few candidate genes methylated out there, but what the field was expecting was to have a global picture of which genes were hypermethylated and in which transformed cells. Our manuscript was the first to report that hypermethylated tumor suppressor genes had a profile of hypermethylation according to the tumor type (i.e., the genes methylated in leukemia are different of those methylated in a breast tumors, and these are different from those in a melanoma, etc.), and second, that all the cellular/molecular pathways had genes affected by promoter hypermethylation, such as DNA repair (BRCA1, MGMT, WRN), cell cycle (p16INK4a, p15INK4b), cell adherence (E-cadherin, EXT-1), apoptosis (DAPK1, TMS1), etc. Another particularly amazing feature of that paper was that we were able to assemble one of the largest collections of primary human tumors in the epigenetic literature.

ST:  Where has this research gone since the publication of the Cancer Research paper?

The original candidate approaches to find new methylated genes took center stage at that time, and they are still pretty successful nowadays, but the eruption of new epigenomic technologies (such as the association of chromatin immunoprecipitation with genomic microarrays or DNA demethylating agents with expression microarrays) is providing further more complete drafts of the hypermethylation events occurring in transformed cells. Thus, we now have more genes hypermethylated in cancer cells, more pathways involved, more tumor types studied, and we can try to guess how many hypermethylated genes are in the human cancer genome.

ST:  I understand you’re currently involved in researching epigenetic modification in twins. What can you tell us about this work? What have you found so far, and where do you hope to take things in the future? 

Although we have in the past much focused our research in DNA methylation, another critical element of the epigenetic layer are histone modifications. Histones "pack" our DNA, but also control its expression and stability. And histones can be chemically modified by methylation (as DNA), but also for acetylation, phosphorylation, and other marks. Thus, epigenetics is really providing a read-out of the genes. In this regard, epigenetics is a critical player in understanding how the same genotype can originate different phenotypes. The change of the color of the skin of the Agouti mouse, related to a change of DNA methylation without any genetic change, is the best example.

Monozygotic twins are another beautiful example (PNAS 2005). These are people with identical DNA sequences but different behavior and predisposition to diseases. We found that as twins get older they start to show a different epigenome. The epigenome of twins is also different if they have different lifestyles, such as smokers vs. non-smokers. The manuscript had a major impact because it transcends the epigenetics field and provides a biological explanation in the topic of nature vs. nurture. We are currently studying if we can identify particular DNA sequences undergoing epigenetic changes in twins in which one has cancer and the other does not, or one has diabetes and the other does not, etc. It is an exciting story.End

Manel Esteller, M.D., Ph.D.
Director, Cancer Epigenetics Laboratory
Molecular Pathology Program
Spanish National Cancer Centre (CNIO)
Madrid, Spain

Dr. Manel Esteller's most-cited paper with 599 cites to date:
Esteller M, et al., "A gene hypermethylation profile of human cancer," Cancer Res. 61(8): 3225-9, 15 April 2001.

Source: Essential Science Indicators

ESI Special Topics: March 2007
Citing URL:

This special topic of Gene Silencing was originally featured in ESI Topics in December 2003. To view the archived Gene Silencing topic, click here.

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