If there is one thing all cancers have in common, it is they have nothing in common. A multi-centre study led by The University of Texas MD Anderson Cancer Center has shed light on why proteins, the seedlings that serve as the incubator for many cancers, can vary from cancer to cancer and even patient to patient, a discovery that adds to a growing base of knowledge important for developing more effective precision therapies.
Liang’s and Mills’ team discovered how a particular type of RNA editing called adenosine to inosine (A-to-I) RNA plays a key role in protein variation in cancer cells. RNA editing is the process by which genetic information is altered in the RNA molecule. Once thought rare in humans and other vertebrates, RNA editing is now recognized as widespread in the human genome.
Since cancer can arise from vastly different protein types and mutations, the promise of individualizing therapies for each patient is reliant upon a better understanding of the protein “genome,” an area of study called proteomics. Understanding the molecular mechanism contributing to protein variation and diversity is a key question in cancer research today, with significant clinical applications for cancer treatment.
“Using data from The Cancer Genome Atlas and the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium, our study provides large-scale direct evidence that A-to-I RNA editing is a source of proteomic diversity in cancer cells,” said Liang. “RNA editing represents a new paradigm for understanding the molecular basis of cancer and developing strategies for precision cancer medicine. If a protein is only highly edited in tumour proteins, but not in normal proteins, then it’s possible that a specific drug could be designed to inhibit the edited mutant protein.”
It has long been known that A-to-I RNA editing allows cells to tweak the RNA molecule resulting in nucleotide sequences which alter DNA “instructions” for how proteins are generated and how they are assembled within the cell.
The researchers demonstrated how A-to-I RNA editing contributes to protein diversity in breast cancer by making changes in amino acid sequences. They found one protein, known as coatomer subunit alpha (COPA), increased cancer cell proliferation, migration and invasion in vitro, following A-to-I RNA editing.
“Collectively, our study suggests that A-to-I RNA editing contributes to protein diversity at least in some cancers,” said Mills. “It is an area of study that deserves more effort from the cancer research community to elucidate the molecular basis of cancers, and potentially developing prognostic and therapeutic approaches.”

M.D. Anderson Cancer Centerwww.mdanderson.org/newsroom/2018/04/rna-editing-study-shows-potential-for-more-effective-precision-cancer-treatment.html

Australian researchers have developed a new risk scoring system for children with leukaemia based on missing DNA fragments or ‘microdeletions’.
The risk score will allow doctors to better predict the chance of relapse of a subgroup of kids currently hidden in a lower risk group.
The international study, led by Australian researchers at Children’s Cancer Institute, discovered that searching for specific gene microdeletions found only in leukaemia, when combined with two other test results, provides doctors with a more accurate way to categorise patient risk than the current approach.
The study tested 475 patients from 6 different children’s hospitals in Australia and New Zealand enrolled on a clinical trial sponsored by ANZCHOG, the Australian and New Zealand Children’s Haematology and Oncology Group.
The patients were all children with non-high-risk B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), a subtype of acute lymphoblastic leukaemia (ALL), the most common childhood cancer with survival rates typically near 90%. Most children with ALL have B-cell precursor acute lymphoblastic leukaemia.
Study leader, Associate Professor Rosemary Sutton, said the most intensive treatment for BCP-ALL patients was usually given to the 11% or so of children in the high-risk category to limit side effects for kids who don’t need it.
“Children in the standard and medium risk category in the study were given less intensive treatment than high-risk patients. But about one in six of them relapsed. Obviously, some children needed more intensive treatment than previously thought – but which ones?” she said.
Prof Sutton said she and her collaborators developed a new kind of risk score which builds on a bone marrow test, the minimal residual disease or MRD test developed at Children’s Cancer Institute, which gives doctors early warning that treatment may not be working.
The MRD test is so sensitive it can detect just one cancer cell in a million bone marrow cells surviving cancer treatment. The test was a huge boon for some children with leukaemia on this same trial, since it alerted doctors that they had a very high risk of relapsing.  Consequently, they were treated very intensively with chemotherapy and bone marrow transplants, and the survival rate of this subgroup doubled. But MRD alone is not enough.
“For the standard to medium risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk”, said Prof Sutton.
“So, we supplemented MRD results with two other pieces of patient information, the presence or absence of specific gene microdeletions and a score called the NCI (National Cancer Institute) risk, based on age and white blood cell count.
“We tested for microdeletions in 9 genes involved in leukaemia and found that two of the genes, IKZF1 (called ‘Ikaros’) and P2RY8-CRLF2, were important predictors of relapse,” she said.
These measures were combined to calculate a risk score for each patient of ‘0’ (no risk factors), to ‘2+’ (several). The study found that children with a ‘2+’ score were most likely to relapse or die within 7 years after treatment started, while those with a ‘0’ score least likely.
The same microdeletions were found to be important for predicting relapse in a cohort of Dutch children with leukaemia and the new scoring system was validated by researchers in The Netherlands.
If the new risk score system is adopted in future, doctors could give children with a ‘2+’ risk more intensive treatment with the aim of improving their survival.
Dr Toby Trahair, paper co-author and oncologist at Kids’ Cancer Centre at Sydney Children’s Hospital, Randwick said the scoring system could make a big difference to the success of childhood leukaemia treatment.
Children’s Cancer Institute
ccia.org.au/missing-dna-fragments-hold-clue-predicting-childhood-leukaemia-relapse/

A new research-based point-of-care test has been developed in Finland for detecting the Lyme neuroborreliosis spread by ticks. The test makes rapid initiation of antibiotic treatment possible for patients with borreliosis, which reduces the post-treatment symptoms related to the disease. At the same time, unnecessary antibiotic treatments can be avoided.
The diagnosis of Lyme neuroborreliosis, a tick-borne infection of the nervous system, relies on infection symptoms, cerebrospinal fluid tests, and detection of the antibody production by the activated immune response.
A Finnish company, Reagena, has developed a new point-of-care test to accompany these methods. The test speeds up the diagnostics and helps to target antibiotic treatment appropriately. The idea for the test was developed by Assistant Professor in Bacteriology, Specialist in Clinical Microbiology Jukka Hytönen from the University of Turku whose research group also validated the test.
The new point-of-care test measures CXCL13 concentration in cerebrospinal fluid, since a high CXCL13 concentration is almost exclusively related to untreated neuroborreliosis. Therefore, the CXCL13 chemokine concentration in the cerebrospinal fluid is a new, important biomarker in the diagnostics of neuroborreliosis. The CXCL13 concentration increases more rapidly in early neuroborreliosis than the antibody concentration in the cerebrospinal fluid, and on the other hand, it declines rapidly after the initiation of antibiotic treatment.
– We have demonstrated that this point-of-care test is extremely efficient. As a result, we suggest that the diagnostic practice for neuroborreliosis in Finland would be reorganised so that the CXCL13 concentration would be measured immediately after the lumbar puncture for cerebrospinal fluid. In the current practice, the concentration results may take up to a week, whereas the new point-of-care test provides quick results, says Hytönen.
With the new test, antibiotic treatment can be targeted to those patients with a high probability of neuroborreliosis. According to Hytönen, it is important to note that a rapidly initiated treatment reduces the post-treatment symptoms related to neuroborreliosis. At the same time, unnecessary treatment initiated just in case can be avoided, which is essential in order to minimise the negative effects related to antibiotics and to prevent the development of antibiotic resistance of bacteria.
Doctors Often Initiate Antibiotic Treatments without Laboratory Results
The clinical pictures of borreliosis vary from local skin infection to infections of the central nervous system, joints or the heart. A typical red rash, the so called erythema migrans lesion, developing and spreading around the tick bite should always be treated with antibiotics without laboratory tests.
– If the rash does not develop or is not diagnosed in the early stages of borreliosis, for example due to its location, the infection may spread to other organs from the skin. Symptoms of the disseminated disease include various neurological symptoms, such as facial nerve paralysis and different types of pain in the limbs and body, notes Hytönen.
The diagnosis of Lyme neuroborreliosis is always clinical-based, meaning it is based on the symptoms experienced by the patient and the doctor’s findings, but laboratory tests are necessary to support the diagnostics. At the moment, the most important laboratory test in the diagnostics of neuroborreliosis is the assay of Borrelia-specific antibodies from the patient’s blood and cerebrospinal fluid.
University of Torkuwww.utu.fi/en/news/news/Pages/New-Point-of-care-Test-Quickly-Detects-Lyme-Neuroborreliosis.aspx

Patient-derived organoids, hollow spheres of cells cultured from tumours, can quickly and accurately predict how patients with pancreatic cancer respond to a variety of treatments, facilitating a precision-medicine approach to the deadly disease. The ability to use organoids as a treatment tool was investigated by an international team of researchers led by Dr. David Tuveson, M.D., Ph.D., Cold Spring Harbor Laboratory (CSHL) Professor and Chief Scientist for The Lustgarten Foundation.
“We’ve identified an approach to prioritize treatment strategies for pancreas cancer patients, with the goal of giving them the best shot at survival and the best shot at a good quality of life,” says Dr. Hervé Tiriac, a researcher in Tuveson’s lab and first author of the paper published today in Cancer Discovery.
With only 8 percent of patients surviving 5 years beyond their diagnosis, pancreatic cancer is one of the deadliest cancer types. Currently, surgical removal of the cancerous tissue is the only effective treatment, but because the disease progresses so quickly, only 15 percent of patients are eligible for the procedure. Surgery-ineligible patients can be treated with drugs or chemotherapy, but patient response is highly varied and there is no good method to determine which treatment is best for any given patient.
For several years, Tuveson has been honing organoid technology to improve research into the disease. Aside from taking only as little as six weeks to grow, a major advantage of organoids is that they can be derived from patients with even very advanced pancreatic cancer, using tiny biopsies.
In this latest development, the Tuveson team generated a library of 66 organoids derived from pancreatic ductal adenocarcinoma (PDAC) tumor specimens at various stages of the disease. The researchers demonstrated that the organoids provide an effective precision-medicine “pharmacotyping,” or drug-testing, pipeline. To do this, “we culture the organoid from the patient’s cancer and then test all possible standard-of-care drugs as well as experimental drugs,” Tiriac explains.
The team assessed RNA levels in individual organoids—a way to measure gene activity—to predict the sensitivity of an organoid to the five chemotherapies currently administered to pancreatic cancer patients. They found that three so-called “signatures” of gene activity in the organoids correctly identified patients who had responded well to these drugs. “The signatures should enable physicians to choose the best initial chemotherapy treatment for pancreatic cancer,” Tuveson says.
Tuveson and his team plan to further refine the gene signatures through additional experiments, and to test in clinical trials the ability of signatures found in organoids to predict the responses of pancreatic cancer patients.

Cold Spring Harbour Laboratory
www.cshl.edu/organoid-profiling-personalizes-treatments-for-pancreatic-cancer/