(Medical Xpress) — Scientists at the Friedrich Miescher Institute for Biomedical Research (FMI) of the Novartis Research Foundation have elucidated the mechanisms underlying the repair of UV-induced damage in DNA, which frequently causes skin cancer. The protein structures additionally determined by these researchers will improve our understanding of how the body protects itself against skin cancer. these studies lay the foundations for the development of a new class of anti cancer agents. The findings were published today in Cell.

Without capturing public attention, the number of new cases of skin cancer is continuously increasing. This type of cancer is now more common than breast, colon and lung cancer combined. no less discouraging is the fact that the number of deaths from skin cancer is also steadily rising – in contrast to the trends observed for many other cancers, where survival rates are improving thanks to effective treatments. But reliable treatments can only be developed if the molecular mechanisms underlying skin cancer are better understood. Here, scientists at the FMI have made an important breakthrough, as they report in the latest issue of Cell.

It is well known that skin cancer arises from damage caused by the sun’s ultraviolet (UV) radiation. This radiation produces mutations in DNA which influence cellular processes, possibly leading to cancer. although the body has various strategies for repairing such damage, the most frequent type of UV lesion turns out to be particularly problematic. in this case, two components of DNA combine to form structures known as cyclobutane pyrimidine dimers (CPDs). these are difficult for the cell’s repair system to detect – partly because they are inconspicuous, given the size of the entire genome, but also because they remain hidden within tightly coiled DNA.

Group Leader Nicolas Thomä and his team at the FMI, working together with colleagues from Kobe and Osaka, have now identified the molecular machinery which allows the cell to recognize lesions not detected by the normal repair system.

In these processes, a key role is played by a protein complex known as DDB1-DDB2-Cul4 ubiquitin ligase. A subunit of this complex, DDB2, specifically recognizes CPDs even if they are located in parts of the DNA which are tightly coiled. The researchers also showed how another protein in this complex, ubiquitin ligase, is activated by the binding of DDB2 to damaged DNA and thus directly triggers degradation processes in cells. Thomä comments: “With this work, for the first time, we’ve traced the steps whereby these common but treacherous genomic UV lesions are recognized and the cells are ultimately eliminated. The mechanism works like molecular sun cream, protecting cells from damage and thus preventing skin cancer.”

But the findings are also relevant to diseases caused by defects in this repair mechanism, such as Cockayne syndrome or xeroderma pigmentosum. in both of these conditions, patients are extremely sensitive to UV radiation. however, they also exhibit other symptoms attributable to the accumulation of DNA errors. As Thomä explains, “The protein structures we’ve determined are a foundation on which specific inhibitors can be developed. Of particular interest here are the ubiquitin ligases, which not only play a role in rare diseases, but have been implicated in the development of many types of cancer.”

More information: Fischer ES, Scrima A, Böhm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thomä NH. (2011). “The molecular basis of CRL4(DDB2/CSA) ubiquitin ligase architecture, targeting and release of signalosome inhibition”. Cell, 147, 5.

Provided by Friedrich Miescher Institute for Biomedical Research

MONTREAL, April 8 (UPI) — Researchers in Canada say they discovered a new gene that predisposes people to both autism and epilepsy.

Study leader Dr. Patrick Cossette of the Universite de Montreal and the research team found a severe mutation of the synapsin gene — SYN1 — in all members of a large French-Canadian family with members suffering from epilepsy and autism.

The analysis of two cohorts of individuals from Quebec made it possible to identify other mutations in the SYN1 gene among 1 percent with autism and 3.5 percent with epilepsy, while several carriers of the SYN1 mutation displayed symptoms of both disorders, Cossette said.

“The results show for the first time the role of the SYN1 gene in autism, in addition to epilepsy, and strengthen the hypothesis that a deregulation of the function of synapse because of this mutation is the cause of both diseases,” Cossette says in a statement. “Until now, no other genetic study of humans has made this demonstration.”

The study, published online in Human Molecular Genetics, says the different forms of autism are often genetic in origin and nearly one-third of people with autism also suffer from epilepsy, but the reason for this co-morbidity is unknown.

Neurofibromatosis is the name for a disorder that affects the skin and nervous system. this disorder is divided into two groups: Neurofibromatosis Type 1 (NF-1, also known as von Recklinghausen’s disease) and Neurofibromatosis Type 2 (NF-2). Type 1 is the most common. this disorder is occurs in approximately 1 in 40,000 people. some experts suspect that it is an inherited disorder which can affect both males and females alike. Mutations of the affected gene can cause the disorder even when no one else in the family has it. only one copy of the affected gene needs to be passed on in order for it to develop. The child of an affected parent has a 50% chance of developing this condition. To diagnose this disease the medical doctor will take a family medical history and do a physical exam. Testing will be done on hearing as well as an EEG. X-rays of the bones and a CT scan or MRI scan of the head may also be done. Neurofibromatosis symptoms usually show up by the age of 10.

Neurofibromatosis symptoms for Type 1 are usually limited to the skin and eyes, nervous system and may present joint and bone manifestations. The common symptoms include markings on the skin called Café au lait (“coffee with milk”). it is common to find 5 or more of these tan patches on the skin. These spots usually develop within the first few years of life. They are commonly found on the scalp, palms of the hands and soles of the feet but they can also occur on other parts of the body. during puberty the spots multiply and darken when exposed to the sun. Such spots can look like freckles only they appear where the sun does not reach, like the arm pits or groin. this freckling is not dangerous but may cause the skin to itch.

Lisch nodules, pigmented bumps found within the iris of the eyes, are associated with Type 1 Neurofibromatosis. The lisch nodules usually do not cause vision problems for most people and usually do not occur until late childhood. These nodules are one of the major signs of neurofibromatosis. The skin can also develop small, rubbery skin lesions called neurofibromas. These tumors consist of an intense co-mingling of nerve cells and fibrous tissue. Bone defects and visual disorders may also be symptoms of this disease. Type 1 can also be complicated by masses on the brain or spinal column.

Neurofiromatosis Type 2 is the rarer form of this disease and is diagnosed in only about 10% of the cases. Symptoms of Neurofibromatosis Type 2 include bilateral acoustic neuromas. These neuromas are tumors on the eight cranial nerves in the brain. Hearing loss, headache, facial weakness and loss of balance are all symptoms of Type 2. Other symptoms can include brain tumors and abnormalities in the eye lenses. Café-au-lait spots are not as common in Type 2 Neurofibromatosis. Skin tumors are not as common in this type either but may also be present. People who are diagnosed with Nerurofibromotosis Type 1 have a better prognosis then those who are diagnosed with Type 2.

There are no treatments for Neurofibromatosis symptoms other than removal of the tumors if they are causing vision loss or other complications. The neurofibromas are small pea-sized nodules that develop along the nerves in the body. They are slow growing and not cancerous. some people with this condition can be afflicted all over their body with these tumors. others may only have a few. People who are diagnosed with this condition are given genetic counseling and made known of their chances for passing this condition to their offspring.

Published on Wed Dec 22 10:16:41 GMT 2010

“Hopes rise for a personalised test for prostate cancer,” according to the Daily Mail. The newspaper says that the blood test routinely used to spot signs of the cancer can be made more accurate if it is used in conjunction with a man’s genetic information.

This news is based on research that looked at improving the predictive power of the prostate-specific antigen (PSA) test commonly used to help detect prostate cancer. When used alone the test can be unreliable as PSA levels, which may indicate cancer, can be raised by a number of factors, such as benign prostate growth or medication use. Equally, not all prostate cancer leads to raised PSA levels. Bearing in mind the limitations of the PSA test, the researchers performed a number of genetic analyses to identify mutations linked to high PSA and prostate cancer. They found that combining genetics with PSA results was more accurate than relying on the test alone.

This type of study is a useful foundation for improving the performance of the PSA test. Further research in this area would need to optimise the performance of the test and assess its ability to reduce prostate cancer deaths before it could be widely used as a screening tool.

The study was carried out by researchers working for deCODE genetics, a private company in Iceland, and collaborators from universities in Cambridge, Spain, Romania, USA and the Netherlands. No funding sources were reported. It was published in the peer-reviewed journal Science Translational Medicine.

The research was covered well by the Daily Mail, which reflected the current problems with the PSA test well and highlighted the preliminary nature of this research.

The prostate specific antigen (PSA) is a protein released by cells in the prostate gland. It can be used to test for prostate cancer as some men with prostate cancer have raised PSA levels. however, while some have suggested that a PSA test could be used as a mass screening tool (given to all men regardless of the presence of symptoms), the issue is controversial as the test only has moderate accuracy. This is because PSA levels naturally vary between men, and PSA is not a very specific marker for prostate cancer, as levels may rise following benign changes to the prostate, some medications or inflammation. This means that in a considerable proportion of men the PSA test fails to detect the disease and in others it gives false positive results.

The researchers report that around 40% of the variation in PSA levels is due to inherited factors. in this research they sought to look at the DNA of a large group of men to see whether they could identify SNPs (single ‘letter’ variations in their genetic code) that were associated with high or low PSA levels. They hoped that any variants identified could be used to adjust PSA test results to account for the inherited variation in PSA levels, making it a better predictor of which PSA increases were specifically due to cancer.

The researchers had access to information on PSA values from 15,757 Icelandic men who had been tested from 1994 to 2009, and did not have prostate cancer. They also had similar samples from the Prostate Testing for Cancer and Treatment trial, which was carried out in the UK. This included data for:

• 524 men with PSA values greater than three nanogrammes (ng)/ml who were diagnosed with prostate cancer after a needle biopsy of their prostate
• 960 men with PSA values between 3 and 10ng/ml prostate cancer who were confirmed as not having prostate cancer after they were given a biopsy
• 454 men with PSA values less than 3ng/ml who had not undergone biopsy

There is no consensus on the best threshold PSA level above which men should be given a biopsy to test for prostate cancer, but PSA levels in the range of 2.5–4ng/ml are commonly used.

With the data from the Icelandic men, the researchers performed a genome-wide association study to look for small variations in the genetic sequences of the men’s DNA, which they could then relate to each man’s PSA values. They then looked at whether any SNPs were associated with having a negative prostate biopsy result in 3,834 men who had biopsies. This was to determine whether men with raised PSA levels due to their genetic make-up were having biopsies that turned out to be unnecessary.

They also looked at whether the SNPs identified were also associated with risk of prostate cancer, by looking at their presence in 5,325 prostate cancer cases and 41,417 unaffected control subjects from Iceland, the Netherlands, Spain, Romania and the United States.

Finally, they used the genetic variations they identified to determine what PSA level was “normal” for each individual and whether accounting for genetics would improve the ability of the PSA test to distinguish between men with and without prostate cancer. They also looked at whether adding genetic information about 23 genetic variants associated with prostate cancer in other studies would also improve the ability of the PSA test to distinguish between men with and without prostate cancer.

In the genome-wide analysis they found that variations in six regions of DNA were associated with men’s PSA levels. They found that the strongest association was for variations in a region of DNA containing the gene that encodes the PSA protein (a site called KLK3). These variations were estimated to account for about 4.2% of the variability in PSA levels in the Icelandic sample, and 11.8% of the variability in the UK sample.

Among 3,834 men who underwent a prostate biopsy, they found that three of these variations were also associated with having a negative biopsy for prostate cancer. The researchers calculated an odds ratio between 1.15 and 1.27, meaning that if a man had a DNA variant in these regions associated with high PSA he would be 15 to 27% more likely to have a negative biopsy result than men who did not.

The researchers then compared the presence of the six variations associated with higher PSA levels in men with and without prostate cancer. They found that four of the variations were also associated with a higher likelihood of prostate cancer. The other two variations were associated with higher PSA levels only.

The researchers then used various models to look at how adding a person’s genetic information might potentially improve the PSA test’s ability to distinguish between men with and without prostate cancer. They found that taking into account just the six variants they had linked to PSA levels improved the performance of the PSA test, but not by much. a model that combined an adjustment for genetic variations associated with high PSA levels and genetic variations associated with prostate cancer risk was the most accurate.

The researchers said that they have identified variations in six DNA regions associated with PSA levels. They said that, of the four models that they produced in order to predict biopsy outcome in men who had high PSA levels, the greatest improvement in prediction accuracy was seen when both the genetic factors associated with high PSA and with increased prostate cancer risk were taken into account.

They said that “for a screening test as important and as widely used as the PSA test, having a better way to interpret the measured serum PSA levels is likely to improve substantially the clinical usefulness of the test”.

This well-conducted research found that it is possible to increase the predictive power of the PSA test by taking into account genetic factors associated with higher levels of PSA and increased risk of prostate cancer. This is a useful step towards improving the performance of the PSA test for identifying prostate cancer. Use of the PSA test alone produces a high rate of false positive and false negative rates, leading to some men undergoing unnecessary biopsies and some cases of prostate cancer being undetected.

The researchers highlighted that they had based their analysis mostly on data from two populations, from Iceland and the UK, and further large prospective studies with mixed populations would be needed to see whether these findings could be applied generally.

Lastly, the models used in this study did not include other factors that may have influenced the results, such as age, ethnicity and family history of the disease. These too would ideally be tested for inclusion in a model aimed at improving how well the PSA test identifies prostate cancer in individuals.

Once they have been optimised, such models would need to be tested in clinical trials to determine whether they have the power to reduce deaths from prostate cancer.

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Gene defects that lead to Rett syndrome, a severe form of autism that predominantly strikes girls, also get jumping genes hopping in neurons, a study in the November 18 Nature shows. if the jumping genes land in parts of the genetic blueprint that are important for brain development or function, they could contribute to the variability of symptoms seen in the disorder.

Rett syndrome is caused by mutations in a gene called MeCP2. Like an orchestra conductor, the protein made by MeCP2 tells genes when to stay silent and when to pipe up. but instead of wielding a baton, MeCP2 does its conducting via a chemical modification to DNA known as DNA methylation. Mutations in the MeCP2 gene lead to the molecular equivalent of a cacophony, with genes making noise when they should be silent. so much molecular noise in the brain leads to speech and movement disorders, repetitive hand-wringing, and other problems associated with Rett syndrome.

Now, researchers show that MeCP2 defects also cause jumping genes to play musical chairs in some brain cells. in brains of people with Rett syndrome a type of jumping gene known as an L1 retrotransposon was more active than in brains of healthy people, says Alysson Muotri, a neuroscientist and molecular biologist at the University of California, San Diego. Retrotransposons are genetic elements that make RNA copies of themselves and then convert to DNA and insert into the genome.

The retrotransposons jumped more only in the brain, Muotri and his colleagues found; hearts taken from people with Rett syndrome showed no more jumping gene activity than those from normal people. that could mean that defects in MeCP2 take the brakes off jumping genes, but an additional factor found only in the brain gets the retrotransposons in gear, Muotri says.

He speculates that some amount of gene jumping is good for the brain, increasing genetic diversity in neurons and possibly making the neurons function better. but too much jumping gene activity increases the likelihood that important genes could get damaged, disabling some brain functions and leading to some of the symptoms of Rett syndrome.

Other scientists aren’t convinced that jumping genes really have a functional consequence. It’s a problem of timing, says Lorenz Studer, a stem cell biologist at the Sloan-Kettering Institute in new York City. Girls with Rett syndrome typically develop normally for the first few years of life and then start to have problems. but jumping genes hop only in dividing cells, such as those in the developing brain. Once neurons reach a mature state they no longer divide, so jumping genes have to make their move long before symptoms of Rett syndrome appear.

Researchers will need to learn to control jumping gene activity so they can do further experiments to show whether hopping contributes to the disease, Studer says. “It might have some important biological function, but until we can switch it on and off we really won’t know.”

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found in: Body & Brain and Genes & Cells