In a landmark multi-country study, Australian researchers have transformed our understanding of the genes that affect our risk of cancer. The researchers uncovered numerous new genetic risk factors for the bone and soft-tissue cancer, sarcoma – and, in a world first for any cancer, they showed that carrying several of these genetic mutations markedly increases an individual’s cancer risk. The findings have immediate implications for how sarcomas and other cancers are treated.

In a landmark study of over 1000 sarcoma patients, the researchers uncovered numerous new genetic risk factors for the cancer – and, in a world first for any cancer type, they showed that carrying two or more of these rare mutations increases an individual’s cancer risk.

Sarcomas are cancers of connective tissues that disproportionately affect the young. They are one of the three leading causes of disease-related death among children and young adults in Australia, and sarcoma survivors are at higher risk of developing a second cancer.

The new findings relating to cancer risk were uncovered through the International Sarcoma Kindred Study (ISKS), an Australian-led international consortium that is exploring the genetic basis of sarcoma in over 1000 individuals – the largest study ever conducted in this disease.

The ISKS team used a ‘gene panel’ of 72 genes to detect mutations in each study participant. They identified mutations in a number of new genes that significantly increase the risk of developing sarcoma, including in the genes ERCC2, ATR, BRCA2 and ATM.

Importantly, in individuals carrying mutations in two genes, the risk of developing sarcoma was measurably higher than in those with a mutation in only one gene. And in carriers of three or more mutations, the risk was greater still.

“This is the first time – in any cancer – that anyone has quantified the effect of multiple rare genetic mutations on cancer risk,” says Professor David Thomas (Head of The Kinghorn Cancer Centre and the Cancer Division of the Garvan Institute of Medical Research), who led the study.

“Until now, we’ve been limited to single-gene thinking, so we tell patients, for instance, that carrying a BRCA1 mutation means their breast cancer risk is higher, or that their risk of sarcoma and other cancers is higher if they’ve got a particular mutation in the p53 gene.

“The study shows us that the landscape of cancer risk is far more complex than that. We can now see that the risk for developing sarcoma is increased through the combined effect of multiple genes, and that the more mutations someone carries, the earlier the onset of cancer.

“These previously invisible effects are at least as large as the impact of mutations in the p53 gene itself, which is currently the strongest known genetic cause of sarcoma.”

Dr Mandy Ballinger (Garvan), who co-ordinates the ISKS globally, says the study will radically change how sarcoma risk is understood.

“It’s well accepted for a few cancers – like breast cancer and bowel cancer – that cancer risk is substantially determined by the genes we inherit from our parents. Our study brings sarcoma into that select group.

“About half the study participants carried at least one of these apparently cancer-promoting mutations, and almost a quarter carried more than one, which really underscores that sarcoma risk is inherited to a large extent from one’s parents.”

“We’ve never been able to identify these at-risk individuals, and their families, before. Now we can,” adds Prof Thomas. “That means we can manage risk better, and help those people to get the care they need, when they need it.”

Garvan Institute www.garvan.org.au/news/news/beyond-single-gene-thinking-garvan-researchers-uncover-complex-genetic-secrets-of-cancer-risk

The 2016 Biotexcel conference ‘Circulating Biomarkers’ will take place at the University of Abertay, Dundee, UK, on 12–13 October, 2016. This is the third such annual meeting and they have fast become one of the highlights of the year for workers in this field.
Circulating biomarkers, such as the various forms of circulating DNA, RNA, tumour cells and exosomes, have proved useful for diagnostics and the monitoring of treatment. Previous meetings have seen presentations about the discovery of circulating biomarkers as well as subsequent validation and blood-biopsy test development. This year, the focus is expanding to include other kinds of least-invasive and non-invasive biomarkers. With its unique format, delegates include participants from science, industry, medicine and engineering and dedicated networking sessions allow broad collaborations between the different disciplines to facilitate the development of new diagnostics.
The meeting includes presentations from leaders of their fields from the UK, Germany and the USA, including
Prof. David Cameron, Edinburgh, UK
Prof. Markus Metzler, Germany
Prof. Craig Beam, USA, and others)
Prof Sue Burchill, Leeds, UK
Prof Colin Palmer, Ninewells Hospital, Dundee, UK
Prof Angie Cox, Sheffield, UK
Dr Clare Vesely, UCL Cancer Institute, London, UK

The topics to be covered are:

• Circulating free tumour DNA
• Circulating micro RNA
• Circulating Tumour Cells
• Fluid & Blood Biopsy Biomarkers & Examples of Translation into the Clinic
• Case Study: “Biomarker to Diagnostic” Pathway
• Non-invasive/Least-invasive biomarkers in Ascites, Hair, Saliva, Urine, CSF, Faeces etc
• PDX – Patient Derived Xenograft models for Biomarkers.

The meeting will also have presentations on the latest technology developments from Analytik Jena, Covaris and Angle Plc.
In addition to presentations, the meeting will also host a panel debate on “How do we break the translational bottle-neck and move circulating biomarkers into the Clinic?”, a poster session and award as well as a complimentary drinks reception hosted by the Lord Provost at City Chambers for all delegates and a 3-course networking dinner at Malmaison.
This meeting is intended to be suitable for researchers and group heads working with circulating biomarkers, researchers working on translational medicine as well as those in the NHS, private labs, pharmaceutical and biotech companies, and service providers.

Please see the Biotexcel webstite (https://biotexcel.com/event/circulating-biomarkers-2016/) for further details of the meeting as well as the speakers and agenda.  Registration can be done through the Biotexcel website or the button on the CLi website www.cli-online.com.

Researchers have identified a new set of genes that may be responsible for the two most common and disabling neurological conditions, stroke and dementia.

The study may help researchers better understand, treat and prevent ischemic and haemorrhagic stroke, and perhaps Alzheimer’s disease and other dementias.

Stroke is the leading neurological cause of death and disability worldwide. Previous studies have looked mainly at genes causing atherosclerosis and genes affecting the function of platelets and clotting processes as risk factors for ischemic stroke (clot obstructing blood flow to the brain). A different set of genes has been associated with haemorrhagic stroke (bleeding into the brain).

Researchers from Boston University School of Medicine looked for new stroke genes using genome wide association as well as meta-analysis. They identified a new gene called FOXF2 which increased the risk of having a stroke due to small vessel disease in the brain. No previous study has identified a gene for the common type of small vessel disease stroke although some genes associated with familial small vessel diseases such as CADASIL are known.

Sudha-Seshadri“Our research has identified a gene affecting another type of ischemic stroke, due to small vessel disease, and also suggests some genes may be associated with both ischemic and haemorrhagic stroke and may act through a novel pathway affecting pericytes, a type of cell in the wall of small arteries and capillaries. Unravelling the mechanisms of small vessel disease is essential for the development of therapeutic and preventive strategies for this major cause of stroke,” explained corresponding author Sudha Seshadri, MD, professor of neurology at BUSM.

According to the researchers small vessel disease not only causes stroke but is also a major contributor to dementia risk, and is associated with gait problems and depression. “Hence, it is exciting that we are beginning to better understand the cause of this very important and poorly understood type of stroke,” she added. Boston School of Medicine

EKF Diagnostics, the global in vitro diagnostics company, announces that it is expanding the distribution of its Procalcitonin LiquiColor Test into Eastern Europe, Middle East and APAC regions. Procalcitonin (PCT) is a marker for bacterial infection and sepsis, a condition that has grown in awareness in recent years. PCT is now widely recognized as an important adjunct marker in sepsis diagnosis which aids in the differentiation between viral and bacterial infections. Sepsis can quickly develop into severe sepsis and septic shock – conditions associated with signs of end-stage organ damage and hypotension. At this stage, risk of death is high and increases drastically the longer the initiation of treatment is delayed. However, if a patient receives antimicrobial therapy within the first hour of diagnosis, their chances of survival are close to 80%. This short window is therefore often referred to as ’the golden hour.’ EKF’s Stanbio Chemistry PCT assay can be used in conjunction with other tests, to rapidly assess initial severity of sepsis within the golden hour.  As it provides quantitative results within ten minutes, it helps physicians to monitor treatment and track improvements over time. The test is CE-marked and will shortly receive FDA approval. It is an open-channel immunoturbidimetric assay that can run with multiple sample types, providing a cost effective solution for many hospital laboratories. “We have started to see significant interest in Asia Pacific for PCT. Here we are working closely with three major distributors covering the Philippines, Indonesia and Vietnam to introduce PCT into hospitals,” said Trevor McCarthy, EKF’s Sales Manager. “As awareness about the severity of sepsis and the importance of early detection grows, we anticipate more and more interest globally in this product. FDA approval will help us build our brand, both in the Asian market and further afield.”
www.ekfdiagnostics.com

Scientists at Baylor College of Medicine, Baylor Genetics, the University of Texas Health Science Center at Houston and Texas Children’s Hospital are combining descriptions of patients’ clinical features with their complex genetic information in a unified analysis to obtain more precise diagnoses of complex diseases, particularly those that involve more than one gene causing the condition.
The researchers anticipate that improved clinical and genetic diagnoses could lead to patients receiving more effective treatments and families benefiting from needed counselling.
“One of the main interests of our lab is to better understand the impact of genetic variation on human health and disease,” said co-first author Dr. Jennifer Posey, assistant professor of molecular and human genetics at Baylor.
“Traditionally, physicians have spoken of a unifying diagnosis, meaning that genetic conditions are due to mutations in only one gene,” said co-first author Dr. Tamar Harel, who was a genetics fellow at Baylor when she was working on this study and currently is a geneticist at Hadassah Medical Center in Israel. “Yet, we see here that two or more genes can be involved in a disease and produce a complex clinical picture. For many in the field, this is a revolutionary idea.”

The challenge of diagnosing diseases with multiple genetic causes
The researchers used whole exome sequencing to analyse all the genes in the genomes of nearly 7,400 unrelated patients with the goal of identifying the genetic cause of their conditions. They found a genetic cause in 2,076 of the 7,374 patients (28 percent); among these patients, 101 (approximately 5 percent) had two or more disease genes involved. If an individual has multiple defective genes, he or she may present with a complex set of clinical features that may lead to an imprecise diagnosis.
“Clinically, multiple genetic causes can be missed because a patient may present with characteristics that overlap those of two different conditions, so the patient can be diagnosed with one or the other,” said Posey. “Alternatively, a patient’s clinical characteristics may not match those of any described condition, so the patient may be diagnosed with what is thought to be a new condition.”
“In these situations, we, as physicians, have to think of the possibility that more than one gene might be involved in the patient’s disease,” said senior author Dr. James R. Lupski, Cullen Professor of Molecular and Human Genetics at Baylor. “Our study shows the limitations of defining a disease according to what we see in the clinic alone. Our work shows the need to consider that a patient may have two or more genetic diseases, not one, and to send for a genomic test to help sort out the patient’s condition and causes of it.”

Paving a future toward more precise multiple genetic diagnoses
“One of the contributions of our work involves utilization of a structured phenotype ontology,” said Posey. “This computational tool allows us to model complex clinical features (phenotypes) that can result when more than one gene is involved, in order to better understand, from the perspective of the physician, how such cases may present in the clinic.”
Furthermore, Dr. Regis James, now at Regeneron Pharmaceuticals, previously created OMIM Explorer while training as a graduate student at BCM. OMIM Explorer is a tool that helps analyse genomic data in the context of the clinical characteristics of the patient. Both James and his thesis advisor and mentor, Dr. Chad Shaw, director of bioinformatics at Baylor Genetics and associate professor of molecular and human genetics at Baylor, were contributors to this work.
“It provides a more complete perspective of how genes and physical traits relate to each other,” said Lupski.
“My colleagues and I anticipate that in the future, geneticists, clinicians and mathematicians will work together using genetic and clinical information to make diagnostic and therapeutic decisions,” said Harel.

Baylor College of Medicine http://tinyurl.com/jm44mr5