EKF Diagnostics subsidiary, Selah Genomics, has announced a major, four-way collaboration with Greenville Health System (GHS, South Carolina), DecisionQ Corporation (Virginia), and BD (Becton Dickinson and Company, New Jersey). Expected to last 18 months, the collaboration aims to unite classic clinical annotations with proprietary next generation sequencing (NGS) technology and artificial intelligence-based decision support algorithms in order to improve clinical decision support in the treatment of colon cancer patients. More than eight out of ten US patients are treated in the community, and as many as 60 percent of all patients with solid tumours do not respond to first-line treatment. This results in further treatment cycles, higher cost, elevated toxicity and, perhaps most importantly, lost time. A tool that significantly improves the prognostication for patients by bringing centre of excellence expertise to any clinical setting is therefore highly desirable. Using its PrecisionPath NGS technology, Selah Genomics will first determine the genetic profiles of tumour samples provided by the Institute for Translational Oncology Research, which is part of GHS’s Cancer Institute.  The samples, from colon cancer patients with known outcomes, will be provided with full clinical annotation. DecisionQ will employ its advanced machine-learning platform to integrate genetic profile data with clinical annotations to produce a model that will improve clinical decisions related to the treatment of colon cancer patients. The research project is being funded in part by BD in return for the first opportunity to license the technology should the collaboration be a success. After the initial collaboration, a clinical trial is planned to validate the research and affirm the effectiveness of the new system as a clinical decision support tool for the community-based setting.

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Scientists have identified a genetic mutation in about 20 percent of colorectal and endometrial cancers that had been overlooked in recent large, comprehensive gene searches. With this discovery, the altered gene, called RNF43, now ranks as one of the most common mutations in the two cancer types.

The investigators from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard said the mutated gene helps control an important cell-signalling pathway, Wnt, that has been implicated in many forms of cancer. They suggest that having a mutation in RNF43 may serve as a biomarker that identifies patients with colorectal and endometrial cancer who could benefit from precision cancer drugs that target the Wnt pathway, although no such drugs have yet been approved.

“Tumours that have this mutation may be telling us that they are dependent on the Wnt signalling pathway, and they will be uniquely sensitive to drugs that inhibit this pathway,” said Charles Fuchs, MD, MPH, an author of the paper and director of the Center for Gastrointestinal Cancer at Dana-Farber. He is also affiliated with Brigham and Women’s Hospital and the Harvard School of Public Health.

In pre-clinical cancer models, tumours with RNF43 mutations have been found to be sensitive to new Wnt pathway inhibitors that are now in clinical trials in humans, according to Marios Giannakis, MD, PhD, who is an attending physician at Dana-Farber and is also a conducting research at the Broad Institute.

The researchers were surprised to find RNF43 mutations in such a significant proportion of colorectal and endometrial cancers because they had not been detected in recent comprehensive searches of tumor DNA conducted by scientists of The Cancer Genome Atlas (TGCA) project.

Authors of the new study believe computer algorithms used by TCGA to parse data from DNA sequencing of tumors may have interpreted the “signal” of the RNF45 mutation as an artifact, and discarded it, much as a legitimate email will sometimes be trapped in a junk filter.

“These mutations occur in repetitive regions of the genome where you often have errors in DNA sequencing, so past algorithms may have been more likely to assume that the RNF43 mutation was an artifact of the sequencing process,” explained Eran Hodis, an MD/PhD student at Harvard Medical School and MIT and also affiliated with the Broad and Dana-Farber. Giannakis and Hodis are co-first authors on the new report.

Other frequently mutated genes in colorectal cancer include APC (75 percent), P53 (50 percent), and KRAS (40 percent).

The new evidence for RNF43 mutations first came from analysis of tumour samples of colorectal cancer that were obtained from two large cohort studies – the Nurses’ Health Study, which has been following 121,000 healthy women since 1976, and the Health Professionals Follow-up Study, which includes 52,000 men enrolled in 1986. About 10 years ago, Fuchs, along with Dana-Farber pathologist Shuji Ogino, MD, PhD, MS, began collecting and studying gastrointestinal tumour samples that had been taken from men and women in the studies who developed cancer. Because these specimens are accompanied by a wealth of data about the patients’ lifestyle, medical history, and other factors, Fuchs calls this collection of tumour samples “a gold mine.”

For the new study, 185 colorectal cancer specimens from this collection were analyzed by whole-exome DNA sequencing at the Broad Institute under the leadership of Levi Garraway, MD, PhD, who is affiliated with Dana-Farber, the Broad, and Brigham and Women’s Hospital, and is corresponding author of the report. The RNF43 mutation was identified in 18.9 percent of the colorectal tumors.

This surprising result prompted the investigators to re-analyse 222 colorectal cancer samples from TCGA project and found the RNF43 mutation in 17.6 percent. The researchers, noting that endometrial cancer is dependent on abnormal Wnt signalling, then re-analysed 248 DNA samples from endometrial cancer that had been previously published by TCGA scientists. They found a strikingly similar proportion – 18.1 percent – of RNF43 mutations in those cancers.

The study authors noted that the discovery of such a significant cancer mutation that hadn’t been picked up in the previous gene hunts shows that carrying out these comprehensive genomic searches continues to have value. Dana-Farber Cancer Institute

After mining the genetic records of thousands of breast cancer patients, researchers from the Johns Hopkins Kimmel Cancer Center have identified a gene whose presence may explain why some breast cancers are resistant to tamoxifen, a widely used hormone treatment generally used after surgery, radiation and other chemotherapy.

The gene, called MACROD2, might also be useful in screening for some aggressive forms of breast cancers, and, someday, offering a new target for therapy, says Ben Ho Park, M.D., Ph.D., an associate professor of oncology in the Kimmel Cancer Center’s Breast Cancer Program and a member of the research team.

The drug tamoxifen is used to treat oestrogen receptor-positive breast cancers. Cells in this type of breast cancer produce protein receptors in their nuclei which bind to and grow in response to the hormone oestrogen. Tamoxifen generally blocks the binding process of the oestrogen-receptor, but some oestrogen receptor-positive cancers are resistant or become resistant to tamoxifen therapy, finding ways to elude its effects. MACROD2 appears to code for a biological path to tamoxifen resistance by diverting the drug from its customary blocking process to a different way of latching onto breast cancer cell receptors, causing cancer cell growth rather than suppression, according to a report by Park and his colleagues.

Specifically, the team’s experiments found that when the gene is overexpressed in breast cancer cells–producing more of its protein product than normal–the cells become resistant to tamoxifen.

One piece of evidence for the gene’s impact was demonstrated when the Johns Hopkins scientists blocked MACROD2’s impact in breast cancer cell cultures by using an RNA molecule that binds to the gene to ‘silence,’ or turn off, the gene’s expression. But the technique only partially restored the cells’ sensitivity to tamoxifen.

To conduct the study, the scientists examined two well-known databases of breast cancer patients’ genetic information, The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium study. Patients who had MACROD2 overexpressed in primary breast cancers at the original breast cancer site had significantly worse survival rates than those who did not, according to an analysis of the patient databases.

With this in mind, the Johns Hopkins scientists suggest that clinicians may be able to look at MACROD2 activity to help them identify aggressive breast cancers at early stages of growth.

The team’s analysis also found that MACROD2 overexpression was present in the majority of metastases in patients with tamoxifen-resistant tumours and in tumour cells that had spread from their original site in the breast. The latter finding, says Park, suggests that tamoxifen resistance caused by the gene might be a process that develops over time as women take the drug.

Finding a small group of a patient’s cancer cells that overexpress MACROD2, he explained, means those cells are likely to be the ‘survivors’ of early treatment with tamoxifen that go on to multiply and cause metastatic tumours. ‘The resultant cells–or the vast majority of them–are now all overexpressing MACROD2, and are the cells that are aggressive and will cause trouble,’ he adds.

Park and his team cautioned that there may be other genetic factors that control tamoxifen resistance, and that nothing in their study should suggest that tamoxifen use should be avoided. EurekAlert

For some children with autism, the ‘Tooth Fairy’ lives in San Diego and wears a white coat. And the Tooth Fairy may offer an answer to what causes their autism, without painful blood draws or skin biopsies.

Alysson Muotri, associate professor of paediatrics and cellular molecular medicine at the University of California, San Diego, created this inventive project in 2012. He realized that rather than force children to undergo upsetting procedures, parents could simply mail one of their child’s baby teeth, which contain enough genetic information to eliminate the need for an in-person visit.

“We announced the project on social networks like Facebook,” Muorti says. “News spread fast.”

The project has roughly 3,500 registered families and 300 teeth so far, and researchers have found five autism candidate genes from the 20 or so cell lines they have sequenced. Several of those genes have never been implicated in autism before.

“We’re finding lots of new genes and sometimes we have no idea what they do, so the next step is to test whether or not those genes are important,” Muotri says. “This type of study may reveal novel pathways in autism and open up the possibility for personalized treatment.”

Autism’s cause is clear in a subset of cases, but the majority of cases are sporadic, meaning they arise from an unidentified combination of genetic and environmental factors.

“Every sporadic individual will likely carry several mutations that probably contribute to a certain extent to the disease, so it is really hard to model that complex phenotype,” Muotri says.

After receiving a tooth, the researchers extract cells from the dental pulp and sequence the whole genome to search for mutations associated with sporadic autism. They then use these dental cells to create induced pluripotent stem (iPS) cells, which can be coaxed into becoming neurons. Muotri says he and his colleagues are the first to use iPS-cell-derived human neurons to model sporadic autism. Simons Foundation Autism Research Institute

A new genetic finding from Duke Medicine suggests that some people who are prone to hostility, anxiety and depression might also be hard-wired to gain weight when exposed to chronic stress, leading to diabetes and heart disease.

An estimated 13 percent of people, all of whom are Caucasian, might carry the genetic susceptibility, and knowing this could help them reduce heart disease with simple interventions such as a healthy diet, exercise and stress management.

“Genetic susceptibility, psychosocial stress and metabolic factors act in combination to increase the risk of cardiovascular disease,” said Elizabeth Hauser, Ph.D. director of Computational Biology at the Duke Molecular Physiology Institute.

Hauser and colleagues analysed genome-wide association data from nearly 6,000 people enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). The MESA study began in 2000 to better understand how heart disease starts, compiling the participants’ genetic makeup as well as physical traits such as hip circumference, body mass index, cholesterol readings, glucose levels, blood pressure and other measures.

In the Duke analysis, the researchers first pinpointed a strong correlation between participants who reported high levels of chronic life stress factors and increased central obesity, as measured by hip circumference.

They then tested genetic variations across the genome to see which ones, in combination with stress, seemed to have the biggest influence on hip circumference. It turns out that variations called single-nucleotide polymorphisms (SNPs) in the EBF1 gene showed a strong relationship with hip circumference, depending on levels of chronic psychosocial stress. What’s more, among those with this particular genotype, hips grew wider as stress levels increased.

“With further analysis, we found a significant pathway from high chronic life stress to wide hip circumference, to high blood glucose and diabetes, to increased cardiovascular disease, notably atherosclerosis,” said Abanish Singh, Ph.D., a researcher in computational biology at Duke and the study’s lead author. “But we found this only in people who were carriers of the EBF1 single-nucleotide polymorphism, and this was limited to participants who were white.”

The researchers reproduced their findings using data from another study, the Framingham Offspring Cohort.

“These findings suggest that a stress reduction intervention, along with diet and exercise, could reduce the risk of cardiovascular disease and may be most effective in individuals with this specific genotype,” said Redford Williams, M.D. one of the study’s senior authors and director of Duke’s Behavioral Medicine Research Center. Duke Medicine