The field of immunotherapy – the harnessing of patients’ own immune systems to fend off cancer – is revolutionizing cancer treatment today. However, clinical trials often show marked improvements in only small subsets of patients, suggesting that as-yet unidentified variations among tumours result in distinct paths of disease progression and response to therapy.
Now, researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC) have demonstrated that genetic variations driving prostate cancer determine the composition of the immune cells that have been found to infiltrate primary prostate tumours. These immune cells, in turn, dictate tumour progression and response to treatment. The data suggest that profiling patients’ tumours based on this new information could lead to more successful clinical trials and tailored therapies for patients.
“We observed that specific genetic events resulted in striking differences in the composition of immune cells present in and around the tumour – results with important therapeutic implications,” said senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC. “Our data may be especially relevant for tailoring immunological therapies and for identifying responsive-patient population.”
The third leading cause of cancer-related death in U.S. men, prostate cancer, is linked to a number of diverse genetic mutations that drive the disease. For example, the loss of the tumour suppressor gene PTEN is a frequent event in prostate cancer and is well known to promote the disease in combinations with a plethora of other mutations. Researchers also know that the tumour’s microenvironment – the blood vessels, immune cells, signalling molecules and other factors that surround the tumour – plays an important role in tumour progression and response to therapy.
Pandolfi’s team – including lead author, Marco Bezzi, a post-doctoral fellow in Pandolfi’s lab – engineered mice models to represent four distinct known genetic variations of human prostate cancer. The models lacked either Pten alone or in combination with other genetic alterations known to drive the disease. When the team analysed the tumours from these mice, they saw profound differences in the types and relative numbers of the immune cells that had accumulated in and around the tumour, what they call the tumours’ “immune landscape”.
For example, specific immune landscapes tumours from the genetic model lacking both Pten and the tumour suppressor gene called Trp53 demonstrated an increased accumulation of myeloid cells, the immune cells that mediate immunosuppression. In stark contrast, tumours from the genetic model lacking Pten and a different tumour suppressor gene called PML lacked intratumoral immune infiltration; that is, the researchers observed no immune cells at all in these tumours, which the scientists dubbed “cold,” or “immune-deserts.” All four mouse models analysed presented very distinctive immune landscapes and these differences were maintained and exacerbated over time.
The research team also demonstrated that these differences in immune cell composition were directly dictated by the tumours themselves because of their genetic variations. Different tumours, they observed, secreted distinct chemical attractants, which in turn recruited – or didn’t recruit, in the case of the immune-desert tumours – different immune cell types into the tumour. Pandolfi and colleagues further demonstrated that these differences hold true in human prostate cancer. Critically, the immune cells recruited to the tumours were found to be essential in supporting the growth and progression of these tumours.
“We observed that when present, these infiltrating immune cells were required for the tumour to thrive and found therapies to block their recruitment to be effective,” said Bezzi. “On the other hand, the cancer genotype characterized by the so-called ‘immune desert’ phenotype, did not respond to such therapies. On this basis, we can predict the tumour response to immunotherapies and tailor treatment modalities to effectively impact tumors that are otherwise extremely aggressive,” he said. 
Thus, because immune cells interact with and also affect tumour response to therapy, these findings may be especially relevant for the development of more precise and effective combinations of immunotherapies and targeted therapies on the basis of the cancer genetic makeup.
Beth Israel Deaconess Medical Centerwww.bidmc.org/News/PRLandingPage/2018/January/Pandolfi-Bezzi.aspx

Genetic mutations in blood cells that have made their way into tumours could be red herrings that mislead physicians looking for genetic changes in tumours that are helping to drive the cancer. This finding is significant because physicians could make misinformed treatment decisions.
University of North Carolina Lineberger Comprehensive Cancer Center researchers and colleagues will report findings at the 2018 American Society of Clinical Oncology Annual Meeting on Monday, June 4, that show that blood cell mutations accounted for as many as 8 percent of the mutations identified in large-scale genetic sequencing efforts at two major academic centres.
“Next-generation sequencing of solid tumours is intended to identify acquired mutations within tumour tissue,” said the study’s first author Catherine C. Coombs, an associate member of UNC Lineberger and an assistant professor in the UNC School of Medicine Division of Hematology/Oncology. “The identification of acquired mutations in blood cells could lead to errors in interpretation of sequencing results.”
For the study, researchers reviewed data from patients with solid tumour cancers who had genetic sequencing tests performed by Foundation Medicine as part of their routine clinical care at the N.C. Cancer Hospital and the Moffitt Cancer Center between 2013 and 2017. They also analysed sequencing results for blood samples. A subset of patients at the N.C. Cancer Hospital had their tumours and their blood sequenced through UNCseq, a genetic sequencing clinical trial run by UNC Lineberger researchers. For patients at Moffitt Cancer Center, they compared Foundation Medicine results to sequencing results from banked blood samples.
The researchers analysed the data to identify mutations more commonly seen in blood cells. They found that “clonal haematopoiesis,” which are acquired mutations in blood cells, accounted for 8 percent of the mutations.
“The presence of clonal haematopoiesis mutations on next-generation sequencing reports from solid tumour biopsies can confound assay interpretation with the risk of misguided application of targeted therapies,” Coombs said.
Researchers say further work must be done to develop standard processes for differentiating mutations that occur in the blood versus the tumour in order to ensure accuracy in the tests for physicians who are using the sequencing results to choose personalized treatments for patients. In addition, the study shows an advantage to “paired” sequencing tests, which evaluate mutations in both the blood and the tumour.

University of North Carolina Lineberger Comprehensive Cancer Center
unclineberger.org/news/mutations-could-contaminate-genetic-analyses

Siemens Healthineers has now confirmed that it has completed the acquisition of Epocal Inc. from Abbott to complete its blood gas portfolio. The closing of the deal occurred October 31, 2017. Financial details of the transaction were not disclosed.
In integrating Epocal Inc.’s offerings into its POC Ecosystem™ solution, Siemens Healthineers enables customized testing offerings based on individual facility needs – whether that is handheld testing, benchtop solutions or central lab applications – to help improve process efficiency. The epoc^® product line will integrate seamlessly into the Siemens Healthineers POC Ecosystem solution for easy connection from many manufacturers’ point-of-care analysers to hospital information systems, providing a flexible, long-term solution.
“Health networks have varying needs for blood gas testing across physicians’ offices, clinics, emergency departments, laboratories and even in ambulances. Having any one solution is limiting and may not meet all patient needs, which is why customized testing solutions are so important for improving patient care,” said Peter Koerte, President, Point of Care Diagnostics, Siemens Healthineers. “With a complete offering for blood gas diagnostics, we can help healthcare providers and point-of-care coordinators improve their workflows by offering the right test in the right setting at the right time.” www.siemens.com/epoc

Researchers have identified specific genes that may trigger the development of sleep problems, and have also demonstrated a genetic link between insomnia and psychiatric disorders such as depression, or physical conditions such as type 2 diabetes. The study was led by Murray Stein of the University of California San Diego and the VA San Diego Healthcare System.
Up to 20 percent of Americans and up to 50 percent of US military veterans are said to have trouble sleeping. The effects insomnia has on a person’s health can be debilitating and place a strain on the healthcare system. Chronic insomnia goes hand in hand with various long-term health issues such as heart disease and type 2 diabetes, as well as mental illness such as post-traumatic stress disorder (PTSD) and suicide.
Twin studies have in the past shown that various sleep-related traits, including insomnia, are heritable. Based on these findings, researchers have started to look into the specific gene variants involved. Stein says such studies are important, given the vast range of reasons why people suffer from insomnia, and the different symptoms and varieties of sleeplessness that can be experienced.
"A better understanding of the molecular bases for insomnia will be critical for the development of new treatments," he adds.
In this study, Stein’s research team conducted genome-wide association studies (GWAS). DNA samples obtained from more than 33,000 soldiers participating in the Army Study To Assess Risk and Resilience in Service members (STARRS) were analysed. Data from soldiers of European, African and Latino descent were grouped separately as part of efforts to identify the influence of specific ancestral lineages. Stein and his colleagues also compared their results with those of two recent studies that used data from the UK Biobank.
Overall, the study confirms that insomnia has a partially heritable basis. The researchers also found a strong genetic link between insomnia and type 2 diabetes. Among participants of European descent, there was additionally a genetic tie between sleeplessness and major depression.
"The genetic correlation between insomnia disorder and other psychiatric disorders, such as major depression, and physical disorders such as type 2 diabetes suggests a shared genetic diathesis for these commonly co-occurring phenotypes," says Stein, who adds that the findings strengthen similar conclusions from prior twin and genome-wide association studies.
Insomnia was linked to the occurrence of specific variants on chromosome 7. In people of European descent, there were also differences on chromosome 9. The variant on chromosome 7, for instance, is close to AUTS2, a gene that has been linked to alcohol consumption, as well as others that relate to brain development and sleep-related electric signalling.
"Several of these variants rest comfortably among locations and pathways already known to be related to sleep and circadian rhythms," Stein elaborates. "Such insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease."
EurekAlertwww.eurekalert.org/pub_releases/2018-03/s-csc030818.php

A USC research team identified 150 proteins affecting cell activity and brain development that contribute to mental disorders, including schizophrenia, bipolar condition and depression.
It’s the first time these molecules, which are associated with the disrupted-in-schizophrenia 1 (DISC1) protein linked to mental disorders, have been identified. The scientists developed new tools involving stem cells to determine chemical reactions the proteins use to influence cell functions and nerve growth in people.
“This moves science closer to opportunities for treatment for serious mental illness,” said Marcelo P. Coba, the study author and professor of psychiatry at the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC.
Schizophrenia affects less than 1 percent of the U.S. population, but has an outsized impact on disability, suicide and premature deaths.
The DISC1 gene was linked to schizophrenia nearly 20 years ago. It controls how nerve cells called neurons develop, as well as how the brain matures. DISC1 also directs a network of signals across cells that can contribute to the disease. Scientists say errors in these chemical reactions contribute to schizophrenia.
But the identity of proteins that DISC1 can regulate is poorly understood, prompting the USC researchers and colleagues from the State University of New York Downstate Medical Center to undertake the research. The challenge was to simulate conditions inside the human brain, Coba explained.
Using stem cells, they conducted assays resembling habitat where DISC1 does its work. They then used gene editing to insert a molecular tag on DISC1, allowing them to extract it from brain cells and identify the proteins with which it associates.
Identifying the proteins that interact with DISC1 in brain cells could lead to understanding how the risk factors for psychiatric diseases are connected to specific molecular functions, Coba explained. The discovery enables researchers to determine specific processes that differ in patients suffering from specific mental illnesses.
This gives researchers specific trails to follow within cells from both healthy patients and those diagnosed with disorders.
Schizophrenia is one of the top 15 leading causes of disability worldwide. People with schizophrenia live an average of nearly 29 years less than those without the disorder, according to the National Institutes of Mental Health (NIMH).
The illness is often accompanied by conditions such as heart disease and diabetes, which contribute to the high premature mortality rate among people with schizophrenia. About 5 percent of people with schizophrenia die by suicide, a rate far greater than the general population, with the highest risk in the early stages of illness, according to the NIMH.

University of Southern California
news.usc.edu/144238/usc-scientists-discover-schizophrenia-gene-roles-in-brain-development/