Researchers have identified a protein critical for the aggressiveness of T-cell leukaemia, a subtype of leukaemia that afflicts children and adults.
The identification of ubiquitin-fusion degradation 1 (UFD1) allows for better understanding what causes leukaemia to progress and become highly aggressive and treatment-resistant, and may lead to a new treatment for this type of cancer.
Leukaemia is a blood cancer that affects individuals of all ages. T-cell is a particularly aggressive subtype of leukaemia which is fatal in 20 percent of children and 50 percent of adults.
Researchers at BUSM conducted combined analyses of patient samples and experimental models of leukaemia that resemble a major subtype of the disease. They found that UFD1 is expressed in this aggressive subtype of leukaemia, and reducing its protein levels by approximately 50 percent inhibited leukaemia development and progression without impacting the overall health of the experimental models.
“Because of its discouraging odds, and because current treatments remain highly toxic to patients, continued research efforts are needed to understand what causes this disease’s aggressiveness and its resistance to treatment, and to identify alternative treatments that are effective but minimally toxic,” explained corresponding author Hui Feng, MD, PhD, assistant professor of pharmacology and medicine at BUSM. “This research identifies the potential of targeting UFD1 to treat aggressive leukaemia without causing high toxicity to normal tissues.”

Boston University school of Medicinewww.bumc.bu.edu/busm/2018/04/27/protein-responsible-for-leukaemias-aggressiveness-identified/

Bone marrow biopsies are the gold standard for diagnosing and monitoring the progression of multiple myeloma, but these procedures are far too invasive to perform at every patient visit. Scientists from the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, however, have shown that two ways to measure multiple myeloma DNA in blood samples provide highly detailed sets of genetic information that agree well not just with each other but with results from bone marrow tests.
“Until now, we haven’t had a good way to measure how multiple myeloma cell populations evolve from precursor stages to diagnosed disease, and then respond to treatments, says Irene Ghobrial, MD, a Dana-Farber medical oncologist. “This is where blood biopsies can make a huge difference—extending our understanding of multiple myeloma, and really giving us a timeline of how the disease progresses and responds to therapy.”
The collaborative research examined blood biopsies that gathered multiple myeloma tumour DNA from two sources. One is circulating free DNA (cfDNA), scraps of DNA released into the bloodstream by dying cells. The other is circulating tumour cells (CTCs)—myeloma cells themselves.
“Our discovery that cfDNA and CTC analyses agree with each other at the comprehensive level is an important finding, because this means that routine genetic profiling of patient tumours from blood would be feasible,” says Ghobrial, co-senior author on a paper reporting the work in Nature Communications.
The blood biopsy analyses followed a two-step sequencing approach, says Viktor Adalsteinsson, PhD, group leader of the Blood Biopsy Team at the Broad Institute and co-senior author on the paper. The first step, developed by his team and called “ultra-low pass” whole genome sequencing, was a cost-effective method to identify blood samples with tumour DNA fraction of at least 5-10%, allowing more comprehensive genetic analysis. In the second step, the researchers performed whole exome sequencing (analysing the protein-coding regions of the genome) on those samples.
The investigators examined cfDNA from 107 patients and CTCs from 56 patients. The scientists then matched up cfDNA with bone marrow data from nine patients, and compared all three forms of biopsy in four additional patients. Overall, the gene profiles overlapped closely—demonstrating about 99% agreement between liquid and bone marrow biopsies for tumour gene mutations, for instance.
Such high levels of agreement suggest that the two forms of liquid biopsy might be used interchangeably to track patients with multiple myeloma, the researchers say, and employing both techniques might further increase the chances of understanding the disease in each patient.

Dana-Farber Institutewww.dana-farber.org/newsroom/news-releases/2018/in-multiple-myeloma–different-types-of-blood-biopsies-match-up-well-with-bone-marrow-tests/

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

Genome-wide association studies (GWAS) have identified more than 150 genetic variations associated with increased risk for breast cancer. Most of these variants are not located in protein-coding gene regions but are assumed to regulate the expression of certain genes.
One way to figure out what these variants are doing is to conduct a cis-eQTL analysis. That’s a way of detecting changes in the expression of genes presumably regulated by a nearby variant.
Using four large-scale data sets from normal and cancerous breast tissue samples, Xingyi Guo, PhD, and colleagues identified 101 candidate breast cancer susceptibility genes with variant-associated gene expression changes. In breast cancer cells grown in culture, the researchers also demonstrated how three genes promoted tumour growth by disrupting normal cell behaviour.
Their findings reveal potential target genes associated with an increased risk of breast cancer and provide additional insights into the underlying genetic and biological mechanisms that drive this common cancer.

Vanderbilt Universitynews.vanderbilt.edu/2018/05/04/new-breast-cancer-targets/

Autism diagnosis is slow and cumbersome, but new findings linking a hormone called vasopressin to social behaviour in monkeys and autism in people may change that. Low vasopressin in cerebrospinal fluid was related to less sociability in both species, indicating the hormone may be a biomarker for autism.
A paper describing the research, which was led by scientists at the Stanford University School of Medicine and the University of California-Davis, was recently published.
“Since autism affects the brain, it’s really hard to access the biology of the condition to know what might be altered,” said Karen Parker, PhD, associate professor of psychiatry and behavioural sciences at Stanford and the lead author of the new study. “Right now, the diagnosis is based on parents’ reports of their children’s symptoms, and on clinicians observing children in the clinic.”
The study’s senior author is John Capitanio, PhD, professor of psychology at UC-Davis.
Autism, a developmental disorder characterized by impaired social abilities, affects 1 in 68 U.S. children. Research has shown that early, intensive behavioural treatment is beneficial. Yet many children don’t receive a timely diagnosis. A biological test, with a specific lab measurement indicating autism, could make diagnosis faster.
Not only is the biology of autism difficult to study in people, but many research animals are unsuited to autism research, Parker said. For instance, mice often fail to show behavioural changes in response to gene mutations that cause autism in people.
So the researchers looked for autism biomarkers in rhesus monkeys, a species whose social capabilities are closer to those of humans. The monkeys had been raised by their mothers in social groups in a primate research colony at UC-Davis. From 222 male animals, the scientists selected 15 with naturally low sociability and compared them with 15 monkeys with naturally high sociability on several biological parameters.
The scientists measured levels of two hormones, oxytocin and vasopressin, in the monkeys’ blood and in their cerebrospinal fluid, which bathes the brain. Both hormones are peptides implicated in a variety of social roles, including parental care and bonds between mates. Some prior studies have hinted that these hormones may also be involved in autism.
Monkeys in the less social group had significantly less vasopressin in their cerebrospinal fluid than monkeys in the more social group. These vasopressin levels accurately predicted the frequency with which individual monkeys participated in social grooming, an important social activity for rhesus monkeys. Vasopressin levels in blood were not different between the two groups. In a second group of 10 monkeys, whose cerebrospinal fluid was sampled four times over four months, the scientists showed that vasopressin levels in the fluid were stable over time.
The researchers also compared vasopressin levels in 14 boys with autism and seven age-matched children without autism. (Vasopressin levels were tested in the children’s cerebrospinal fluid, which was collected via lumbar puncture for medical reasons; their families agreed to allow some fluid to be used for research.) Children with autism had lower vasopressin levels than children without autism, the study found.
“What we consider this to be at this point is a biomarker for low sociability,” Capitanio said.
The researchers now want to test a larger group of monkeys for vasopressin levels to determine whether the hormone levels can distinguish monkeys with low social abilities from others with a wide range of social ability. And they want to explore whether low vasopressin could be detected before symptoms of impaired social ability emerge.
“We don’t know if we see really low cerebrospinal fluid vasopressin before you see behavioral symptoms of autism,” Parker said. “Ideally, it would be a risk marker, but we haven’t studied that yet.”

Stanford School of Medicinemed.stanford.edu/news/all-news/2018/05/scientists-find-possible-autism-biomarker-in-cerebrospinal-fluid.html