A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition

  1. Manel Esteller3,*
  1. 11Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute
  2. 2Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
  3. 3Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL)
  4. 4Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute
  5. 5Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute
  6. 6Cancer Research Laboratory, Faculty of Medicine, University of Iceland
  7. 7Department of Bioinformatics and Geno, Centro de Investigacion Principe Felipe
  8. 89Institute for Research in Biomedicine (IRB Barcelona)
  9. 9Centre Nacional d’Anàlisi Genòmica (CNAG)
  1. * Corresponding Author:
    Manel Esteller, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Avda. Gran Via s/n Km 2.7, L’Hospitalet, Barcelona, Barcelona, 08908, Spain mesteller{at}idibell.cat

Epithelial-to-mesenchymal transition (EMT) is a plastic process in which fully differentiated epithelial cells are converted into poorly differentiated, migratory and invasive mesenchymal cells and it has been related to the metastasis potential of tumors. This is a reversible process and cells can also eventually undergo mesenchymal-to-epithelial transition (MET). The existence of a dynamic EMT process suggests the involvement of epigenetic shifts in the phenotype. Herein, we obtained the DNA methylomes at single-base resolution of MDCK cells undergoing epithelial-to-mesenchymal transition (EMT) and translated the identified differentially methylated regions (DMRs) to human breast cancer cells undergoing a gain of migratory and invasive capabilities associated with the EMT phenotype. We noticed dynamic and reversible changes of DNA methylation, both on promoter sequences and gene-bodies in association with transcription regulation of EMT-related genes. Most importantly, the identified DNA methylation markers of EMT were present in primary mammary tumors in association with the epithelial or the mesenchymal phenotype of the studied breast cancer samples.

  • Received December 23, 2013.
  • Revision received June 20, 2014.
  • Accepted July 8, 2014.

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Posted by admin - August 23, 2014 at 9:03 am

Categories: Lymphoma   Tags: , , , ,

Risk of urinary tract infections after prostate biopsy highest in men with prior infections or significant comorbidities


Transrectal ultrasound guided biopsy is the gold standard for detecting prostate cancer, but international reports have suggested that the number of risks associated with the procedure is increasing. In a new nationwide population-based study, Swedish researchers found that six percent of men filled a prescription for antibiotics for a urinary tract infection within 30 days after having a prostate biopsy, with a twofold increase in hospital admissions over five years, reports The Journal of Urology®.

Earlier studies reported serious adverse events after prostate biopsy including febrile urinary tract infection and urosepsis in one to four percent of men, despite the use of prophylactic antibiotics. There have also been reports that chronic conditions such as diabetes, benign prostatic hyperplasia (BPH), and a history of urinary tract infection increase the risk of infections.

To estimate the incidence of infection after prostate biopsy and assess risk factors for infection and 90-day mortality in Sweden, researchers looked at records of more than 51,000 men registered in the Swedish Prostate Cancer database who underwent transrectal ultrasound guided prostate biopsy between 2006 and 2011. They also compiled data from the National Prostate Cancer Register (NPCR) of Sweden, which captures more than 96 percent of all newly diagnosed prostate cancers in the country.

“We aimed to estimate the frequency and severity of infectious complications in men diagnosed with prostate cancer after prostate biopsy by examining how many men filled prescriptions for antibiotics related to urinary tract infections, rates of hospitalization within 30 days, and death due to infection,” says lead investigator Karl-Johan Lundström, MD, Department of Surgical and Perioperative Sciences, Urology, Andrology, Umeå University, Ostersund, Sweden. “We also capitalized upon the unique nationwide cross-linked health care databases in Sweden to perform a more comprehensive evaluation of potential risk factors for infectious complications,” he adds.

Of the men who filled a prescription for urinary tract antibiotics within 30 days of biopsy, 54 percent filled the prescription in the first week after biopsy. One percent of men were hospitalized with a urinary tract infection.

Between 2006 and 2011 the number of men obtaining an antibiotic prescription after biopsy decreased, whereas the number who were hospitalized increased. No significant increase in 90-day mortality was observed, however.

The strongest risk factors for an antibiotic prescription were multiple comorbidities, particularly diabetes, and prior infection. Overall, approximately two percent of the men had a urinary tract infection during the six months before biopsy.

“Our data show that severe infections with hospitalization after prostate biopsy are increasing in Sweden. The rate of hospital admission increased twofold during this five-year period. However, the risk of dying of an infection after prostate biopsy is very low,” observes Dr. Lundström. “The risk of post-biopsy infection is highest among men with a history of urinary tract infections and those with significant comorbidities. The increasing risk of hospitalization is concerning and highlights the importance of carefully evaluating the indications for biopsy especially in men at increased risk of infection,” he concludes.

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Posted by admin - August 23, 2014 at 9:00 am

Categories: Cervical Cancer   Tags: , , , , , , , , , ,

Bob Marley, genomics, and a rare form of melanoma

Our researchers are working to understand the genetic complexity underlying the rare type of skin cancer that killed Bob Marley.

In May 1981 the music world lost a legend when reggae artist Bob Marley died after a four-year battle with a melanoma skin cancer that started on his toe.

This may seem strange, as melanoma is usually associated with fair skin and exposure to UV radiation from the sun. But in fact Marley was diagnosed with a rare but fast-growing type of skin cancer known as acral melanoma, which isn’t strongly linked to UV exposure.

Named after their location – the hairless acral skin on the palms of the hands, soles of the feet and under the nails – these tumours are very different from the majority of melanomas that arise elsewhere on the hairy bits of the skin, which are known as ‘cutaneous’ melanomas.

There are a couple of other unusual types of melanoma – ocular (uveal) melanomas that grow in the eye, and mucosal melanomas that start on the mucus-producing surfaces of the body, such as in the mouth or up the nose. These are also much rarer than cutaneous melanoma.

What ties these tumours together and makes them all melanomas is that they each arise from rogue melanocytes – pigment producing cells found all over the skin. The pigment they produce, melanin, is mainly responsible for skin and hair colour, and helps to protect us from UV rays from the sun.

But while their biological roots may be the same, there are key differences between them, affecting how they grow and spread in the body, and how they respond to treatment.

So to find out more about these unusual cancers – and work out how best to approach treating them – our researchers at the Manchester Cancer Research Centre, led by Professor Richard Marais, have been delving into the world of genetics.

We’re Genome-ing

When Bob Marley died in the 80s, the sort of genetic analysis techniques now available to Professor Marais and his team would have seemed like something out of Back to the Future.

Modern advances in researchers’ ability to analyse, or ‘sequence’ DNA are revolutionising our understanding of many types of cancer. It’s now possible to ‘read’ all the genetic information within the cells of a tumour (its genome) in a matter of days, revealing the catalogue of gene faults they carry.

And in a new paper published in the journal Pigment Cell & Melanoma Research, Professor Marais and his team have looked in detail at the genomes of acral melanoma samples taken from five patients. They bolted this on to information from three other acral melanomas they had previously analysed (making eight in total), and compared the findings with data from five mucosal, 12 uveal and 25 cutaneous melanomas.

Their analysis revealed that the genetic faults in acral melanoma are very different from these other types of skin cancer.

The DNA in cutaneous melanoma is characterised by tens of thousands of ‘typos’ in the DNA code – individual single changes scattered around the cancer’s DNA. In contrast, most of the acral melanomas had fewer of these single letter genetic faults. Instead, large chunks of DNA had broken off and reattached elsewhere – a bit like large sections of text being randomly cut and pasted throughout a document. Other sections were missing altogether.

Homing in on specific genes, the researchers discovered that these distortions in acral melanomas led to mutations in several of the ‘usual suspects’, which have also been implicated in other types of cancer. These include genes called BRAF and KIT, which are already known to be faulty in cutaneous melanoma.

Professor Marais and his team also spotted a selection of other faulty genes in various acral melanoma samples, including mutations in genes called p53, PTEN, NRAS, and APC – all of which are well-known culprits that can cause cells to grow out of control, leading to cancer.

So what makes these tumours distinct?

How Jamaica melanoma?

The researchers also uncovered some intriguing information about the potential causes of different types of melanoma. It’s been known for some time that cancers on hairy skin carry the characteristic hallmarks of damage wrought in their DNA by ultraviolet (UV) rays from the sun or sunbeds. It’s also clear from large studies that UV is a major risk factor for these tumours.

But although Professor Marais and his team previously found evidence of this kind of DNA damage in a sample taken from an acral melanoma patient a couple of years ago, and in cells from acral melanomas grown in the lab, the acral tumour samples in this latest study didn’t have the hallmarks of UV damage. This suggests that while UV exposure may play a role in some patients’ acral melanomas, it’s not a major driving factor.

The other interesting finding from their analysis is that acral and mucosal melanomas seem to be broadly similar when it comes to the amount and type of genetic damage – with both having less than cutaneous melanomas – while uveal melanomas are different again. These eye cancers seem to have particularly low levels of genetic chaos within them, and the faults they do have probably come from a different source.

Stir it up

In the world of music it would probably be seen as over simplistic to group all artists under one umbrella. Even within reggae-based music pioneered by Marley and other artists there is a plethora of genres from roots to rockers, dub to dancehall.

As we’ve written about before, in the world of cancer research and therapy we’re moving away from a ‘one size fits all’ approach to how we target the disease, focussing instead on the underlying genetic makeup of an individual patient’s disease.

This research, and more like it going on around the world, is prising open the ‘black box’ of cancer and challenges us to think in a new way. Understanding the individual genetic faults driving different types and subtypes of cancer is key to treating it more effectively in the future.

In particular, finding out about the specific faulty genes that drive different types of melanoma is vital for finding more effective ways to treat these aggressive diseases. For example, the drug vemurafenib (also known as Zelboraf) targets faults in the BRAF gene, and other such gene-targeted therapies are in development.

But this isn’t without its challenges. We’re now finding out that cancer’s genetic complexities can vary throughout a patient’s body, and even within the same tumour. And these faults can also change and evolve as the disease grows, helping it develop resistance to treatment.

There’s also a lot of work to be done to figure out how best to use new genetically-targeted therapies to improve survival (something we’re starting to do in our new Lung Matrix Trial). And given the recent headlines about the cost of cancer drugs, this is clearly a political and financial challenge as well as a scientific one.

But with every new research paper, we’re building a growing map of this complex set of diseases that we call cancer. And we believe that it will lead us to new cures that can make a difference to patients everywhere.

Kat

Reference:

  • Furney, S, et al. (2014). The mutational burden of acral melanoma revealed by whole-genome sequencing and comparative analysis Pigment Cell & Melanoma Research DOI: 10.1111/pcmr.12279

 Image from Wikimedia Commons

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Posted by admin - August 23, 2014 at 8:59 am

Categories: Vulvar Cancer   Tags: , , , ,

Web-based app developed to predict glioma mutations


A new web-based program developed by University of Kentucky Markey Cancer Center researchers will provide a simple, free way for healthcare providers to determine which brain tumor cases require testing for a genetic mutation.

Gliomas – a type of tumor that begins in the brain or spine – are the most common and deadly form of brain cancer in adults, making up about 80 percent of malignant brain cancer cases. In some of these cases, patients have a mutation in a specific gene, known as an IDH1 mutation – and patients who have this tend to survive years longer than those who do not carry the mutation.

The program, developed by UK researchers Li Chen, Eric Durbin, and Craig Horbinski, uses a statistical model to accurately predict the likelihood that a patient carries the IDH1 mutation and requires screening. Healthcare providers need only answer four questions in the application.

Gliomas are often tested for IDH1 mutation following surgery to remove the tumor, but undergoing this type of testing often requires stringent insurance pre-approvals due to rising healthcare costs, Horbinski says.

“Currently, there are no universally accepted guidelines for when gliomas should be tested for this mutation,” Horbinski said. “Obtaining insurance pre-approval for additional molecular testing is becoming more commonplace, and this program will assist healthcare providers with an evidence-based rationale for when IDH1 screening is necessary.”

Additionally, Horbinski notes that the program will help conserve research dollars by helping brain cancer researchers narrow down which specific older gliomas in tumor banks – previously removed in a time before IDH1 testing was routine – should be tested as data for research projects.

Horbinski’s research on the program was published in a recent issue of Neuro-Oncology. The work was funded through a grant from the National Cancer Institute, the Peter and Carmen Lucia Buck Training Program in Translational Clinical Oncology, and the University of Kentucky College of Medicine Physician Scientist Program.

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Posted by admin - August 23, 2014 at 8:59 am

Categories: Laryngeal Cancer   Tags: , , , ,

Trim32 facilitates degradation of MYCN on spindle poles and induces asymmetric cell division in human neuroblastoma cells

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Posted by admin - August 23, 2014 at 8:30 am

Categories: Thymus Cancer   Tags: , , , , , , , , , , , ,

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