Breast cancer cells that spread to other parts of the body break off and leave the primary tumour at late stages of disease development, scientists from the Wellcome Trust Sanger Institute and their collaborators have found.
The results show that catching and treating breast cancer before it spreads is a realistic goal. It also opens the door to predicting which drugs will work against breast cancer that has already spread.
It is estimated that 35,000 people in the UK have metastatic breast cancer. The survival rates are poor: around 15 out of 100 women will survive advanced breast cancer for five years or more after diagnosis. The prognosis has not improved in the past 20-30 years.
Most of the research into breast cancer has focused on primary breast cancer, and there is little understanding of the biology underpinning breast cancer that has spread to other parts of the body, known as metastatic cancer. This is in part due to the difficulty in acquiring samples of tumours that have spread to other tissues.
In this study, scientists investigated how breast cancer evolves from the original tumour in the breast to tumours that have spread, or metastasised. It has been controversial whether the breast cancer cells that spread to other parts of the body break off and leave the primary tumour in the breast at early or at late stages of cancer development. The team found that most of the genetic changes in the original breast tumour were also present in the metastatic tumours, showing that the cancer cells spread late in disease development.
This shows promise for breast cancer patients as diagnosing and treating the breast cancer at early stages means there is a greater chance of preventing cancer cells spreading to other tissues, such as the lungs, brain and bone.
“As the cells that cause the spread of breast cancer leave relatively late, it means they are still quite similar to the cells in the primary tumour. Therefore by studying the genome of the primary breast cancer tumour, in the future we may be able to predict what cells that might have spread ‘look’ like, and potentially which treatments they will respond to.”
Dr Lucy Yates, first author from the Wellcome Trust Sanger Institute and Guys and St Thomas’ NHS Trust
In the retrospective study, the team sequenced the DNA of 299 tumours from 170 patients with breast cancer that either returned in the remaining breast – local relapse – or had spread – metastatic breast cancer.
Researchers found that in the time between breast cancer patients being diagnosed with primary cancer and the diagnosis of metastasis, the breast cancer cells had gained genetic changes, or mutations, that increased the aggressiveness of the tumour. This may explain why metastatic breast cancer is currently difficult to treat.
“Most women who have metastatic breast cancer do not have another biopsy of the cancer, and rarely have it analysed using genetic sequencing. In this study we found that in some cases, the metastatic tumours had particular genetic changes that could be targeted with treatments. We would not have seen these mutations by sequencing the primary tumour alone. Our results suggest that it should be more routine to biopsy the metastasis and have it genetically analysed in order to open up clinical trials of treatment options for metastatic breast cancer.”
Studies are now open to recruit patients with metastatic breast cancer across Europe – these studies will first extend the analysis performed here to many more patients, but the ultimate goal is to build a platform for identifying an appropriate clinical trial of new treatments for each patient with metastatic breast cancer.

Sanger Institute
www.sanger.ac.uk/news/view/new-genetic-analysis-reveals-late-spread-breast-cancer-and-backs-key-role-early-diagnosis

Mayo Clinic researchers have identified a new cause of treatment resistance in prostate cancer. Their discovery also suggests ways to improve prostate cancer therapy.
In the publication, the authors explain the role of mutations within the SPOP gene on the development of resistance to one class of drugs. SPOP mutations are the most frequent genetic changes seen in primary prostate cancer. These mutations play a central role in the development of resistance to drugs called BET-inhibitors.
BET, bromodomain and extra-terminal domain, inhibitors are drugs that prevent the action of BET proteins. These proteins help guide the abnormal growth of cancer cells.
As a therapy, BET-inhibitors are promising, but drug resistance often develops, says Haojie Huang, Ph.D., senior author and a molecular biologist within Mayo Clinic’s Center for Biomedical Discovery. Prostate cancer is among the most diagnosed malignancies in the United States. It is also the third leading cause of cancer death in American men, according to the American Cancer Society. Because of this, says Dr. Huang, improving treatments for prostate cancer is an important public health goal.
In the publication, the authors report SPOP mutations stabilize BET proteins against the action of BET-inhibitors. By this action, the mutations also promote cancer cell proliferation, invasion and survival.
“These findings have important implications for prostate cancer treatment, because SPOP mutation or elevated BET protein expression can now be used as biomarkers to improve outcome of BET inhibitor-oriented therapy of prostate cancer with SPOP mutation or BET protein overexpression,” says Dr. Huang.
The publication presents four major discoveries:
BET proteins (BRD2, BRD3 and BRD4) are true degradation substrates of SPOP.
SPOP mutations cause elevation of BET proteins in prostate cancer patient specimens.
Expression of SPOP mutants leads to BET-inhibitor resistance and activation of the AKT-mTORC1 pathway that promotes cancerous cell growth and survival.
Co-administration of AKT inhibitors overcomes BET inhibitor resistance in SPOP-mutated prostate cancer.

Mayo Clinichttp://tinyurl.com/y8phuv4s

Researchers at the Stanford University School of Medicine have linked chronic fatigue syndrome to variations in 17 immune-system signalling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity.
The findings provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years.
“Chronic fatigue syndrome can turn a life of productive activity into one of dependency and desolation,” said Jose Montoya, MD, professor of infectious diseases, who is the study’s lead author. Some spontaneous recoveries occur during the first year, he said, but rarely after the condition has persisted more than five years.
The study’s senior author is Mark Davis, PhD, professor of immunology and microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection.
“There’s been a great deal of controversy and confusion surrounding myalgic encephalomyelitis (ME) CFS — even whether it is an actual disease,” said Davis. “Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.”
Many, but not all, ME/CFS patients experience flulike symptoms common in inflammation-driven diseases, Montoya said. But because its symptoms are so diffuse —sometimes manifesting as heart problems, sometimes as mental impairment nicknamed “brain fog,” other times as indigestion, diarrhea, constipation, muscle pain, tender lymph nodes and so forth — it often goes undiagnosed, even among patients who’ve visited a half-dozen or more different specialists in an effort to determine what’s wrong with them.
The sporadic effectiveness of antiviral and anti-inflammatory drugs has spurred Montoya to undertake a systematic study to see if the inflammation that’s been a will-o’-the-wisp in those previous searches could be definitively pinned down.
To attack this problem, he called on Davis, who helped create the Human Immune Monitoring Center. Since its inception a decade ago, the centre has served as an engine for large-scale, data-intensive immunological analysis of human blood and tissue samples. Directed by study co-author Holden Maecker, PhD, a professor of microbiology and immunology, the centre is equipped to rapidly assess gene variations and activity levels, frequencies of numerous immune cell types, blood concentrations of scores of immune proteins, activation states of intercellular signalling models, and more on a massive scale.
This approach is akin to being able to look for and find larger patterns — analogous to whole words or sentences — in order to locate a desired paragraph in a lengthy manuscript, rather than just try to locate it by counting the number of times in which the letter A appears in every paragraph.
The scientists analysed blood samples from 192 of Montoya’s patients, as well as from 392 healthy control subjects. The average age of patients and controls was about 50. Patients’ average duration of symptoms was somewhat more than 10 years.
Importantly, the study design took into account patients’ disease severity and duration. The scientists found that some cytokine levels were lower in patients with mild forms of ME/CFS than in the control subjects, but elevated in ME/CFS patients with relatively severe manifestations. Averaging the results for patients versus controls with respect to these measures would have obscured this phenomenon, which Montoya said he thinks may reflect different genetic predispositions, among patients, to progress to mild versus severe disease.
When comparing patients versus control subjects, the researchers found that only two of the 51 cytokines they measured were different. Tumour growth factor beta was higher and resistin was lower in ME/CFS patients. However, the investigators found that the concentrations of 17 of the cytokines tracked disease severity. Thirteen of those 17 cytokines are pro-inflammatory.
TGF-beta is often thought of as an anti-inflammatory rather than a pro-inflammatory cytokine. But it’s known to take on a pro-inflammatory character in some cases, including certain cancers. ME/CFS patients have a higher than normal incidence of lymphoma, and Montoya speculated that TGF-beta’s elevation in ME/CFS patients could turn out to be a link.
One of the cytokines whose levels corresponded to disease severity, leptin, is secreted by fat tissue. Best known as a satiety reporter that tells the brain when somebody’s stomach is full, leptin is also an active pro-inflammatory substance. Generally, leptin is more abundant in women’s blood than in men’s, which could throw light on why more women than men have ME/CFS.

Stanford Medicinehttp://tinyurl.com/y7agngxn

Autism spectrum disorder affects approximately one out of every 68 children in the United States. Despite expansive study, the origin and risk factors of the complex condition are not fully understood.
To better understand the root causes, an international team led by researchers at OHSU in Portland, Oregon, has applied a new systematic analysis to a cohort of 2,300 families who have a single child affected with autism. The study focused on identifying and characterizing low-lying genetic mutations that may have been missed in previous research, given these mutations are only present in a fraction of the bulk DNA of an individual.
Known as postzygotic mosaic mutations, or PMMs, these genetic changes occur after the conception of the human zygote during the development cycle of a foetus. An individual will contain a mosaic – or assortment – of mutated and non-mutated cells with the level of mosaicism depending on the time and location of the mutation’s occurrence. This emerging class of genetic risk factors has recently been implicated in various neurologic conditions, however, their role in more complex disorders, such as autism, has been unclear.
By comparing genetic sequencing data of these families — part of the Simons Simplex Collection, a permanent repository of precisely characterized genetic samples — the research team determined that approximately 11 percent of previously reported new mutations affecting a single DNA base, which were thought to have be present at the time of human conception, actually show evidence of the mutation occurring during the development process.
“This initial finding told us that, generally, these mosaic mutations are much more common than previously believed. We thought this might be the tip of a genetic iceberg waiting to be explored,” said the study’s principal investigator Brian O’Roak, Ph.D., an assistant professor of molecular and medical genetics in the OHSU School of Medicine.
To investigate this possibility, a custom approach — leveraging next generation sequencing and molecular barcodes– was developed to both identify these low-level mutations, and also validate that they are, in fact, real and not technological artifacts. With this more sensitive method, the rate of potentially PMMs increased to 22 percent of the new mutations present in children. 
The researchers then compared the rates of PMMs that result in different predicted effects on the genome in affected children and their unaffected siblings. This lead to an unexpected finding that so-called “silent” mosaic mutations were enriched in the affected children, contributing risk to approximately 2 percent of the individuals with autism in this cohort. These types of mutations are generally believed to be neutral, as they don’t alter the genetic coding of proteins. However, the team found evidence that these mutations might actually be altering how genetic messages are stitched together.
The study also found preliminary evidence that mosaic mutations that alter the protein code of genes essential for development, or genes that resist mutations, are also enriched in individuals with autism. This contributes risk to an additional 1 to 2 percent of individuals with autism. Many of the PMMs occurred in some of the most highly validated autism risk genes identified to date, further suggesting that these mutations are contributing to autism genetic risk. Due to this, the research team believes that overall, mosaic mutations may contribute to autism risk in 3 to 4 percent of this cohort.

OHSU School of Medicine
news.ohsu.edu/2017/08/31/study-identifies-new-genetic-risk-factor-for-developing-autism-spectrum-disorder

A gene called triggering receptor expressed on myeloid cells 2, or TREM2, has been associated with numerous neurodegenerative diseases, such as Alzheimer’s disease, Frontotemporal lobar degeneration, Parkinson’s disease, and Nasu-Hakola disease. Recently, a rare mutation in the gene has been shown to increase the risk for developing Alzheimer’s disease.
Independently from each other, two research groups have now revealed the molecular mechanism behind this mutation. Their research sheds light on the role of TREM2 in normal brain function and suggests a new therapeutic target in Alzheimer’s disease treatment.
Alzheimer’s disease, just like other neurodegenerative diseases, is characterized by the accumulation of specific protein aggregates in the brain. Specialized brain immune cells called microglia strive to counter this process by engulfing the toxic buildup. But as the brain ages, microglia eventually lose out and fail to rid all the damaging material.
TREM2 is active on microglia and enables them to carry out their protective function. The protein spans the microglia cell membrane and uses its external region to detect dying cells or lipids associated with toxic protein aggregates. Subsequently, TREM2 is cut in two. The external part is shed from the protein and released, while the remaining part still present in the cell membrane is degraded. To better understand TREM2 function, the two research groups took a closer look at its cleavage. They were led by Christian Haass at the German Center for Neurodegenerative Diseases at the Ludwig-Maximilians-University in Munich, Germany, and Damian Crowther of AstraZeneca’s IMED Neuroscience group in Cambridge, UK together with colleagues at the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto and the Cambridge Institute for Medical Research, University of Cambridge, UK.
Using different technological approaches, both groups first determined the exact site of protein shedding and found it to be at amino acid 157. Amino acid 157 was no unknown. Only recently, researchers from China had uncovered that a mutation at this exact position, referred to as p.H157Y, increased the risk of Alzheimer’s disease. Together, these observations indicate that protein cleavage is perturbed in the p.H157 mutant and that this alteration promotes disease development.
As a next step, Haass and Crowther’s groups investigated the biochemical properties of the p.H157Y mutant protein more closely. They found that the mutant was cleaved more rapidly than a healthy version of the protein. "Our results provide a detailed molecular mechanism for how this rare mutation alters the function of TREM2 and hence facilitates the progression of Alzheimer’s disease," said Crowther.
While most TREM2 mutations affect protein production, the mechanism behind p.H157Y is somewhat different. The p.H157Y mutation allows the protein to be correctly manufactured and transported to the microglia cell surface, but then it is cleaved too quickly. "The end result is the same. In both cases, there is too little full-length TREM protein on microglia," said Haass. "This suggests that stabilizing TREM2, by making it less susceptible to cleavage, may be a viable therapeutic strategy."

EurekAlert
www.eurekalert.org/pub_releases/2017-08/e-st-083017.php