The Beatson Institute of Cancer Research, Bearsden, Glasgow, hosted ‘Circulating Biomarkers 2015’, a Biotexcel conference and workshop. The role of circulating biomarkers in early diagnosis and treatment monitoring is gaining momentum with kits for analysing DNA and RNA from circulating tissue already on the market, and liquid biopsy products in development. The analysis of circulating biomarkers allows less expensive and less invasive screening of patients, and so would enable the early diagnosis of disease and hence timely treatment, for example in pancreatic cancer where presentation typically occurs too late for a cure to be achieved. Also, monitoring of treatment in, for example, breast cancer patients by screening of circulating tumour cells will allow clinicians to make better and quicker decisions about the best therapy for the patient.
In the now familiar format, the meeting included a mix of lectures, a networking workshop, a panel debate, and technology presentations.  The lectures included, among others, presentations on the analysis of circulating tumour DNA (Prof. Charles Coombes, Imperial College London, UK; Dr Gerhardt Attard, Institute of Cancer Research and the Royal Marsden, Surrey, UK), RNA (Prof. Sue Burchill, Leeds Institute of Cancer and Pathology, UK), circulating tumour cells (CTCs) (Dr Vera Cappelletti, National Cancer Institute, Milan, Italy; Dr François-Clément Bidard, Institut Curie, Paris, France) and micro RNA (Dr Alberto Rocci, Manchester Royal Infirmary, Manchester, UK). Other talks discussed the potential of metabolomic biomarkers in cancer (Dr Oliver Maddocks, Beatson Institute for Cancer Research, Glasgow, UK) and how to use a variety of biomarkers and other parameters for the evaluation of the complex  situation of ageing and lifespan (Prof. Paul Shiels, University of Glasgow, Glasgow, UK).
The technology presentations included talks on technology for the enrichment of circulating cell-free DNA (Dr Vipulkumar Patel, Analytik Jena), coupling the CellSearch system (CellSearch) and DEPArray platform (Silicon Biosystems) to isolate single CTCs (by Dr Francesca Fontana (Silicon Biosystems) and targeted biomarker detection by MassARRAY (Dr Malcolm Plant, Agena Bioscience).
The panel debate was centred around the question, ‘CTCs vs. cfDNA vs. miRNA vs. mRNA: which is better and why?’ but perhaps the more interesting discussion that evolved was on the ethics of biomarker analysis (Is it ethical to screen for a condition where there is no treatment ?) and the practicalities of screening (How do we screen for conditions that need to be caught before the presentation of symptoms?). Additionally, the meeting provided many networking opportunities and the benefit of such discussion will, no doubt, be borne out by the development and continuation of new and existing collaborations. A very profitable meeting for all involved.

The largest genetic study of atopic dermatitis ever performed permitted a team of international researchers to identify ten previously unknown genetic variations that contribute to the development of the condition. The researchers also found evidence of genetic overlap between atopic dermatitis and other illnesses, including inflammatory bowel disease.

Atopic dermatitis, a type of eczema, afflicts approximately one out of every five children and one out of every twelve adults. Though knowledge of the genome is crucial to assessing the likelihood that an individual will develop atopic dermatitis, most genes responsible for the condition have not yet been discovered.

The team of international researchers that conducted the largest genetic study of atopic dermatitis to this point pooled data obtained from 377,000 subjects in 40 different projects around the world.

 “We identified ten new genetic variations, making a total of 31 that are currently known to be associated with atopic dermatitis,” says Bo Jacobsson, a professor at Sahlgrenska Academy who was a member of the team. “Of particular interest is that each of the new ones has a role to play in regulation of the immune system.”
The researchers found evidence of genetic overlap between atopic dermatitis and other illnesses, including inflammatory bowel disease.

 “While the new variations contribute in only a small way to the risk of developing atopic dermatitis, knowing about them will raise our awareness about the mechanisms of the various diseases,” Professor Jacobsson says. “Our ultimate hope is that additional treatment methods will emerge as a result.”
Although the importance of genetic factors in the pathogenesis of atopic dermatitis had already been established, the sheer size of this study allowed researchers to fine tune their understanding and obtain more information about the ways that autoimmune mechanisms run amok as the disease develops.

A total of 21,399 cases of European, African, Japanese and Latino ancestry were first compared in 22 different studies with 95,464 controls. The findings were then replicated in 18 studies of 32,059 cases and 228,628 controls.

“Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis” was published in Nature Genetics online on October 19. University of Gothenburg

Scientists at the Salk Institute have uncovered a molecule whose mutation leads to the aggressive growth of a common and deadly type of lung cancer in humans.

This enzyme, called EphA2, normally polices a gene responsible for tissue growth. But when EphA2 is mutated, the Salk team discovered, cellular systems can run amok and quickly develop tumours. The new work suggests that EphA2 could be a new target for a subset of lung cancer, which affects non-smokers as well as smokers, and is the leading cause of cancer-related deaths worldwide.

 “Sometimes there are hundreds of mutations in the genes of a patient’s tumors, but you don’t know whether they are drivers of the disease or by-products,” says senior author Inder Verma, professor of genetics and holder of Salk’s Irwin and Joan Jacobs Chair in Exemplary Life Science. “We found a new way by which to identify cancer suppressor genes and understand how they could be targeted for therapies.”

Two gene mutations in particular are known to spur the growth of human tumours: KRAS and p53. Though both genes have been heavily studied, they are difficult to therapeutically target, so the Salk team decided to look at genes that might police KRAS and p53 instead.

The researchers narrowed in on the 4,700 genes in the human genome related to cellular signalling–specifically, genes that have the ability to tamp down cell growth and proliferation. Then the team adapted a genetic screening technique to quickly and efficiently test the effect of these thousands of genes on tumour development. In animal models, the Salk team found that 16 of these cell-signalling genes produced molecules that had a significant effect on KRAS- and p53-related tumours.

Of these 16 molecules, one especially stood out: the EphA2 enzyme, originally discovered in the lab of another Salk scientist, Tony Hunter. Previously, EphA2’s significance in lung cancer was unclear, but the team discovered that its absence let KRAS-associated tumours grow much more aggressively.

“With a mutation in KRAS, a tumour forms in 300 days. But without EphA2, the KRAS mutation leads to tumours in half the time, 120 to 150 days,” says Verma, who is also an American Cancer Society Professor of Molecular Biology. “This molecule EphA2 is having a huge effect on restraining cancer growth when KRAS is mutated.” Mutated KRAS is a common culprit in approximately 10 to 20 percent of all cancers, particularly colon cancer and human lung cancer.

 “Since activating EphA2 led to the suppression of both cell signalling and cell proliferation, we believe that the enzyme might serve as a potential drug target in KRAS-dependent lung adenocarcinoma,” says Narayana Yeddula, a Salk research associate and first author of the paper. Salk Institute for Biological Studies

Future Science Group (FSG) have announced the publication of a new article in Future Science OA, reporting data demonstrating the possibility of measuring 10 biomarkers relevant to autism spectrum disorder in adult saliva.

With more than 70 biomarkers shown to be of relevance to autism, it is doubtful that a single biomarker will be of use in diagnosis and determination of severity. As such, it is important to develop a clinically relevant and measurable panel of biomarkers. Saliva presents an intriguing opportunity, as it is non-invasive and considered less stressful for patients than collection of urine or blood.

The study, by Helen V Ratajczak (Edmond Enterprises, CT, USA) and Robert B Sothern (University of Minnesota, MN, USA), analysed levels of 10 biomarkers previously noted to be pertinent to autism in saliva from 12 neurotypical, healthy adults. The utilized method was developed with simplicity in mind, with a view towards enabling future testing in autistic adults and, potentially, in children.

“This research is timely, as we desperately need biomarkers of autism spectrum disorder,” commented Francesca Lake, Managing Editor. “The findings, while preliminary, bring us a step closer to our ultimate goal of being effectively able to diagnose and treat autism. We look forward to further studies in more patients, and in those affected by autism.”

“Saliva was chosen because its collection causes the least stress (and the least effect on biomarker concentration),” explained Ratajczak. “Similar results were obtained when 6 men and 6 women read instructions, and an hour later after having instructions given by the principal investigator. Therefore, saliva can be collected by literate individuals without added instruction.  In addition, the elapse of an hour between collections did not significantly alter marker concentrations.” The researchers hope to design future studies to further this research, looking to aid diagnosis of autism and determination of severity, and brings us closer to a subject-specific treatment. Future Science

University of Utah chemists devised a new way to detect chemical damage to DNA that sometimes leads to genetic mutations responsible for many diseases, including various cancers and neurological disorders.

“We are one step closer to understanding the underlying chemistry that leads to genetic diseases,” says Cynthia Burrows, distinguished professor and chair of chemistry at the university. “We have a way of marking and copying DNA damage sites so that we can preserve the information of where and what the damage was.”

Jan Riedl, a University of Utah postdoctoral fellow and the study’s first author, says 99 percent of DNA lesions – damage to the chemical bases known as A, C, G and T that help form the DNA double helix – are repaired naturally. The rest can lead to genetic mutations, which are errors in the sequence of bases and can cause disease. The new method can “identify and detect the position of lesions that lead to diseases,” he says.

Burrows says: “We are trying to look for the chemical changes in the base that can lead the cell to make a mistake, a mutation. One of the powerful things about our method is we can read more than a single damaged site [and up to dozens] on the same strand of DNA.”

The chemists say their new method will let researchers study chemical details of DNA lesions or damage. Such lesions, if not repaired naturally, accumulate over time and can lead to mutations responsible for many age-related diseases, including colon, breast, liver, lung and melanoma skin cancers; clogged arteries; and neurological ailments such as Huntington’s disease and Lou Gehrig’s disease.

“A method capable of identifying the chemical identity and location in which lesions appear is crucial for determining the molecular etiology [cause] of these diseases,” Burrows and colleague write in their study.

The new method for finding DNA lesions combines other, existing techniques.

First, the researchers find the damage and cut it out of the DNA the same way a cell does naturally, using what is called “base excision repair,” the discovery of which won a Nobel Prize in Chemistry this year for Tomas Lindahl, a scientist in England.

Second, an “unnatural base pair” is inserted at the snipped-out DNA damage site to label it. Instead of natural base pairs C-G and A-T, the Utah chemists used a so-called third or unnatural base pair invented by chemists at the Scripps Research Institute in California. Burrows says her study demonstrates the first practical use of that invention.

Third, the DNA with the damage site labelled by an unnatural third base pair is then amplified or copied millions of times using a well-known existing method called PCR, or polymerase chain reaction. Burrows says the new study’s key innovation was to use base excision repair to snip out the damage and then to insert the unnatural base pair at the damage site, making it possible to make millions of copies of the DNA – a process that normally would be prevented by the damage.

Fourth, another chemical label, named 18-crown-6 ether, is affixed to the unnatural base pair on all the DNA strands, which are then read or sequenced using a kind of nanopore sequencing developed a few years ago by Burrows and Utah chemist Henry White. Such sequencing involves determining the order and location of bases on a DNA strand – including damage sites labell ed by unnatural bases – by passing the strand through a molecule-size pore or nanopore.

People are born with their genome or genetic blueprint of 3 billion base pairs, “and then stuff happens,” Burrows says. “There’s damage from oxidative stress due to inflammation and infection, too much metabolism, or environmental chemicals.”

The new method seeks “molecular details that define how our genome responds to what we eat and the air we breathe, and ends up being healthy or not,” she says. University of Utah