The term intellectual disability covers a large number of clinical entities, some with known cause and others of uncertain origin. For example Down syndrome is due to an extra copy of chromosome 21 and Rett syndrome is in part caused by a mutation in the control switch gene called MeCP2.

In other cases the mechanisms by which they are produced are not clearly identified. It is the case of most of those disorders classified under the large umbrella of autism. An study by Manel Esteller, director of the Program Epigenetics and Cancer Biology (PEBC) of the Bellvitge Biomedical Research Institute (IDIBELL), ICREA researcher and Professor of Genetics at the University of Barcelona , has discovered a mechanism that identifies a cause of intellectual disabilities in these puzzling cases.

‘We have analysed the genome of 215 patients with mental retardation, autism or Rett syndrome, in which they had not found any genetic alteration in the genes classically associated with these clinical conditions, to see if we could find a molecular cause. And this process has allowed us to detect a new mutated gene that could be causing these disorders. ‘He explained Manel Esteller.

‘Specifically, the identified gene is called JMJD1C (Jumonji Domain Containing 1C) and is an epigenetic gene which its normal function is to control the activity of other genes. Only a small percentage of mental retardation of unknown origin is due to mutation of this gene. This finding suggests that many genes with low frequency disturbance are responsible for cases with unknown cause. They have demonstrated that this gene joins the MeCP2 gene so it could also contribute to cases of atypical Rett Syndrome ‘says Esteller. IDIBELL

Cancer DNA circulating in the bloodstream of lung cancer patients can provide doctors with vital mutation information that can help optimise treatment when tumour tissue is not available, an international group of researchers has reported at the European Lung Cancer Conference (ELCC) in Geneva, Switzerland.

The results have important implications for the use of cancer therapies that target specific cancer mutations, explains Dr Martin Reck from the Department of Thoracic Oncology at Lung Clinic Grosshansdorf, Germany, who presented the findings at the conference.

Testing for the presence of these mutations in the tumour itself is not always possible, however studies have suggested that DNA from the tumour that circulates in the bloodstream of patients may provide similar information.

The large international ASSESS study aimed to compare the ability of blood testing to detect EGFR mutations with the more standard method of testing the tumour itself.

“We were really asking a question on behalf of patients,” Reck said: “Is there a valid test that can identify an EGFR mutation and give me the opportunity for superior treatment, even if my lung tumour is not accessible for bronchoscopy or CT-guided biopsy? And, are the results of this blood test in agreement with the results of the ‘gold-standard’ tissue test?”

Overall, the study included 1162 matched tissue and blood samples. Comparison of the outcomes of EGFR testing in the two techniques showed an 89% rate of agreement between the blood test and tissue test. Plasma testing identified about half of the patients with EGFR mutations, compared to tissue testing (a sensitivity of 46%).

The tests in this study were not performed in specially selected central labs, but in local labs that are used for daily clinical routine. “This is important, because it does reflect the clinical reality and not a ‘virtual’ trial reality,” Reck said.

“The results mean that for patients who do not have accessible tumour tissue, plasma testing for EGFR mutation turns out to be an attractive option to offer these patients adequate targeted treatment,” Reck added.

Commenting on the study, Dr Rafael Rosell, from the Catalan Institute of Oncology, Barcelona, Spain, expert on the ESMO Faculty on Lung cancer, said: “Cell-free DNA detected in the bloodstream of cancer patients represents an excellent tool to examine genetic alterations that are usually  found through tumour tissue testing. This represents one of the most astonishing phenomena in biology.”

“The results of this study validate that the presence of EGFR mutations in circulating DNA from plasma or serum (fractions obtained from whole blood) can be detected in around half of the patients.”

Already, since this study was performed, improvement of techniques have seen the sensitivity of tests for EGFR mutations in circulating tumour DNA increase further, Rosell noted.

“This work paves the way for further studies and expands the routine use of examining mutations such as EGFR mutations as part of cancer patient care,” Rosell said. European Society for Medical Oncology

Normal skin contains an unexpectedly high number of cancer-associated mutations, according to a study. The findings illuminate the first steps cells take towards becoming a cancer and demonstrate the value of analysing normal tissue to learn more about the origins of the disease.

The study revealed that each cell in normal facial skin carries many thousands of mutations, mainly caused by exposure to sunlight. Around 25 per cent of skin cells in samples from people without cancer were found to carry at least one cancer-associated mutation.

Ultra-deep genetic sequencing was performed on 234 biopsies taken from four patients revealing 3,760 mutations, with more than 100 cancer-associated mutations per square centimetre of skin. Cells with these mutations formed clusters of cells, known as clones, that had grown to be around twice the size of normal clones, but none of them had become cancerous.

‘With this technology, we can now peer into the first steps a cell takes to become cancerous,’ explains Dr Peter Campbell, a corresponding author from the Wellcome Trust Sanger Institute. ‘These first cancer-associated mutations give cells a boost compared to their normal neighbours. They have a burst of growth that increases the pool of cells waiting for the next mutation to push them even further.

‘We can even see some cells in normal skin that have taken two or three such steps towards cancer. How many of these steps are needed to become fully cancerous? Maybe five, maybe 10, we don’t know yet.’

The mutations observed showed the patterns associated with the most common and treatable form of skin cancer linked to sun exposure, known as cutaneous squamous cell carcinoma, rather than melanoma, a rarer and sometimes fatal form of skin cancer.

‘The burden of mutations observed is high but almost certainly none of these clones would have developed into skin cancer,’ explains Dr Iñigo Martincorena, first author from the Sanger Institute. ‘Because skin cancers are so common in the population, it makes sense that individuals would carry a large number of mutations. What we are seeing here are the hidden depths of the iceberg, not just the relatively small number that break through the surface waters to become cancer.’

Skin samples used in this study were taken from four people aged between 55 and 73 who were undergoing routine surgery to remove excess eyelid skin that was obscuring vision. The mutations had accumulated over each individual’s lifetime as the eyelids were exposed to sunshine. The researchers estimate that each sun-exposed skin cell accumulated on average a new mutation in its genome for nearly every day of life.

‘These kinds of mutations accumulate over time – whenever our skin is exposed to sunlight, we are at risk of adding to them,’ explains Dr Phil Jones, a corresponding author from the Sanger Institute and the MRC Cancer Unit at the University of Cambridge. ‘Throughout our lives we need to protect our skin by using sun-block lotions, staying away from midday sun and covering exposed skin wherever possible. These precautions are important at any stage of life but particularly in children, who are busy growing new skin, and older people, who have already built up an array of mutations.’

Recent studies analysing blood samples from people who do not have cancer had revealed a lower burden of mutations, with only a small percentage of individuals carrying a cancer-causing mutation in their blood cells. Owing to sun exposure, skin is much more heavily mutated, with thousands of cancer-associated mutations expected in any adult’s skin.

The results demonstrate the potential of using normal tissue to better understand the origins of cancer. The Cancer Genomics group at the Sanger Institute will continue this work with larger sample numbers and a broader range of tissues to understand how healthy cells transition into cancerous cells. Sanger Institute

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), in cooperation with colleagues at the University of Zurich and the Ruhr-Universität Bochum, have for the first time successfully tested a new tumour diagnosis method under near-real conditions. The new method first sends out an antibody as a ‘spy’ to detect the diseased cells and then binds to them. This antibody in turn attracts a subsequently administered radioactively labelled probe. The scientists could then clearly visualize the tumour by utilizing a tomographic method. This procedure could improve cancer treatment in the future by using internal radiation.

The human immune system forms antibodies that protect the body from pathogens. Antibodies can also, however, be produced in a laboratory to precisely bind to tumour cells. They are used in cancer research to detect and fight malignant tumours. For example, antibodies can serve as transport vehicles for radionuclides, with which the affected regions can be visualized or can even be damaged. Until recently, a stumbling block has been their large molecular mass. “This causes them to circulate in the body for too long before they reach the diseased cells,” explains Dr Holger Stephan from the Institute of Radiopharmaceutical Cancer Research at HZDR. ‘This is a disadvantage because organs that are not affected by the disease are exposed to radiation. It also makes the exact localization of the tumour in the body more difficult because the resulting images are less sharp.”

Together with colleagues at the University of Zurich and the Ruhr-Universität Bochum, the researchers from Dresden therefore chose an alternative strategy. “By using what is known as ‘pre-targeting’, the antibodies’ task is divided into two steps,” Dr Kristof Zarschler, a member of Stephan’s team, explains. “In a figurative sense, we first send spies out in advance, over a longer period of time, to scout out the enemy – the tumour cells. The ‘spies’ then share their position with their troops, which we subsequently send out so that they will directly reach their target with the radioactive material.” The researchers fall back on the cetuximab antibody as the scout, which binds selectively to the epidermal growth factor receptor (EGFR). In various types of tumours, there is an increase in this molecule’s formation or it might be found in a mutated form, which then leads the cells to grow and multiply uncontrolled.

The Dresden researchers combined the antibody with a peptide nucleic acid (PNA) derivative which Prof Gilles Gasser and Prof Nils Metzler-Nolte developed together with their respective working groups in Switzerland and Germany. “It is a very stable synthetic variant of DNA,’ says Holger Stephan. “Similar to a single strand of DNA, it consists of a certain sequence of the four organic bases. Complementary PNA with matching sequence binds to it in a highly precise and stable manner.” During their experiments, the scientists first injected the PNA-EGFR antibody into tumour-bearing mice and gave this “spy” time to accumulate at the tumour site. They then administered the PNA counterpart, labelled with the radioactive substance technetium-99m. “Images we took using single photon emission computed tomography show that both the antibody and its counterpart located each other quickly,” says Zarschler, pleased with the results.

The tumour could thus be clearly visualized within a short period of time. “Furthermore, the radioactively labelled probes had already disappeared from the bloodstream after sixty minutes,” explains Holger Stephan. “This minimizes radioactive exposure risk of healthy body tissue. By pre-targeting, we can overcome limitations of conventional, radioactively marked antibodies.” According to the researchers, it will, however, take some time before the combination of PNA antibodies and their matching PNA counterparts can be used in diagnosing tumours in humans.

“Our results however show that the PNAs we tested are suitable candidates for further preclinical studies,” Stephan sums up. They could provide new possibilities not only for visualizing diseased cells but also for fighting them. “If the method is proven to work, it could also be used to transport therapeutically effective radioactive substances to the tumour in order to irradiate it from within and ultimately damage it.” Helmholtz-Zentrum Dresden-Rossendorf