Pseudoachondroplasia (PSACH) is a severe inherited dwarfing condition characterised by disproportionate short stature, joint laxity, pain, and early onset osteoarthritis. In PSACH, a genetic mutation leads to abnormal retention of cartilage oligomeric matrix protein (COMP) within the endoplasmic reticulum (ER) of cartilage-producing cells (chondrocytes), which interferes with function and cell viability. In a report, investigators describe how this protein accumulation results in “ER stress” and initiates a host of pathologic changes. These findings may open up new ways to treat PSACH and other ER-stress-related conditions.

“This is the first study linking ER stress to midline 1 protein (MID1), a microtubule stabilizer that increases mammalian target of rapamycin complex 1 (mTORC1) signalling in chondrocytes and other cell types. This finding has significant implications for cellular functions including autophagy, protein synthesis, and potentially cellular viability. These results identify new therapeutic targets for this pathologic process in a wide spectrum of ER-stress disorders such as type 2 diabetes, Alzheimer disease, and tuberculosis,” explained Karen L. Posey, PhD, Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

PSACH symptoms generally are recognized beginning at two years of age. Patients with PSACH have normal intelligence and cranio-facial features. PSACH is caused by mutations in the gene encoding the cartilage oligomeric matrix protein (COMP). ER stress occurs when abnormal (unfolded or misfolded) COMP (MT-COMP) accumulates in the rough endoplasmic reticulum of chondrocytes. Rough ER, the portion of ER displaying ribosomes, is the network of membranous tubules within cells associated with protein and lipid synthesis and export.

In previous studies, Dr. Posey and her colleagues have investigated chondrocyte pathology in the growth plates of dwarf mice that express MT-COMP, in cultured rat chondrosarcoma (RCS) cells that express human MT-COMP, as well as in cultured cartilage nodules from PSACH patients. The mice replicate many of the clinical features and chondrocyte pathology reported in patients with PSACH.

In the current study, the researchers showed increased levels of MID1 protein in chondrocytes from the mutant dwarf mice as well as in cells from human PSACH patients. They also found that ER-stress-inducing drugs increased MID1 signalling, although oxidative stress did not.

The up-regulation of MID1 was associated with increased mTORC1 signalling in the growth plates of the dwarf mice. Rapamycin decreased intracellular retention of MT-COMP and decreased mTORC1 signaling. The mTOR pathway is activated during various cellular processes (eg, tumor formation and angiogenesis, insulin resistance, adipogenesis, and T-lymphocyte activation) and is dysregulated in diseases such as cancer and type 2 diabetes.

The results of this work show that MID1, mTORC1 signalling, the microtubule network, protein synthesis, inflammation, and autophagy form a complex multifaceted response to protein accumulation in the ER when clearance efforts fail and MID1 may act as a pro-survival factor.
EurekAlertwww.eurekalert.org/pub_releases/2018-12/e-iuo121018.php

Modern science and data sharing converged to underpin a study led by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, that identified a gene associated with a rare condition that results in physical and intellectual disabilities of children.

The results suggest that rare variants in the gene DDX6 are associated with a significant disruption in the development of the central nervous system, governing such basic skills as the ability to walk and talk.

“One of the most powerful revelations of this study is the identification of pathogenic mutations in DDX6; a gene not previously linked to childhood disorders and one which appears to play a key role in early brain development,” said Chris Balak, a research associate in TGen’s Neurogenomics Division, and the study’s lead author.

Balak zeroed in on DDX6 by comparing the sequencing results from a 5-year-old Arizona girl who was seen at TGen’s Center for Rare Childhood Disorders (the Center) with those identified in large population databases and to the genomes of her parents, who are healthy. Following this revelation, and preliminary findings posted on a website shared by investigators worldwide, TGen identified four similar cases: two in the U.S., and one each in France and the Netherlands.

These children’s conditions were characterized by intellectual disability, developmental delay, speech and feeding difficulties, low muscle strength with difficulties walking, mild-to-moderate cardiac anomalies, and specific facial features.

“Something we are quite proud of with this work is our combined effort with other physi-
cians and scientists in Europe to demonstrate that changes in this gene cause this rare syndrome in multiple patients,” said Dr. Matt Huentelman, TGen Professor of Neruogenomics, Scientific Director of the Center, and one of the study’s senior authors. “Collectively, our clinical and laboratory data describe a new brain development syndrome caused by genetic changes in DDX6.”
TGenwww.tgen.org/news/2019/august/15/tgen-identifies-ddx6-linked-to-disabilities/

A new calculator developed by the University of Exeter will help clinicians classify whether a patient has type 1 or type 2 diabetes, ensuring they get the best treatment and reducing complications.

The calculator uses a model that takes into account available data about the patient, as well as blood test results. It can be used to identify if a person is likely to have type 1 diabetes, to reduce misdiagnosis. Former Prime Minister Theresa May was initially diagnosed with type 2 diabetes. Only when tablet treatment failed to work was she re-diagnosed with type 1.

It is often difficult for clinicians to diagnose which type of diabetes a patient has. While blood tests such as antibodies against the cells that make insulin, or a person’s genetic risk of type 1 diabetes may help diagnosis,  these tests do not give a diagnosis on their own, and may be interpreted very differently depending on whether or not a person has other features of type 1 diabetes. The new calculator, currently available in beta format, combines available information from blood tests with a person’s age of diagnosis and BMI for a personalised medicine approach. The calculator was developed by researchers at the universities of Exeter, Oxford and Dundee.

The new calculator will build on the success of a similar calculator previously developed at Exeter, to help clinicians determine whether a patient has the diabetes subtype MODY, caused by a single gene. The online calculator has been used by more than 100,000 people, with more than 9,000 people downloading the calculator phone app Diabetes Diagnostics, which will be updated to include the new calculator. New research recently presented at the European Association for the Study of Diabetes conference in Barcelona has shown that almost half of all referrals sent to the UK diagnostic laboratory for MODY now report using the calculator, and those that report using the calculator have a higher detection rate compared with those that do not.
Dr Angus Jones, of the University of Exeter Medical School, who led the research, said: “The right diagnosis in diabetes is absolutely crucial to getting the best outcomes for patients, as treatment is very different in different types of diabetes. However in some people it can be very difficult to know what type of diabetes they have. Our new calculator can help clinicians by combining different features to give them the probability a person will have type 1 diabetes, and assess whether additional tests are likely to be helpful.”
The new beta format calculator can be accessed here: www.diabetesgenes.org/t1dt2d-prediction-model/
University of Exeterwww.exeter.ac.uk/news/research/title_754422_en.html

A new blood test in development has shown ability to screen for numerous types of cancer with a high degree of accuracy, a trial of the test shows.

The test, developed by GRAIL, Inc., uses next-generation sequencing technology to probe DNA for tiny chemical tags (methy-lation) that influence whether genes are active or inactive. When applied to nearly 3,600 blood samples – some from patients with cancer, some from people who had not been diagnosed with cancer at the time of the blood draw – the test successfully picked up a cancer signal from the cancer patient samples, and correctly identified the tissue from where the cancer began (the tissue of origin). The test’s specificity – its ability to return a positive result only when cancer is actually present – was high, as was its ability to pinpoint the organ or tissue of origin, researchers found.

The new test looks for DNA, which cancer cells shed into the bloodstream when they die. In contrast to “liquid biopsies,” which detect genetic mutations or other cancer-related alterations in DNA, the technology focuses on modifications to DNA known as methyl groups. Methyl groups are chemical units that can be attached to DNA, in a process called methylation, to control which genes are “on” and which are “off.” Abnormal patterns of methylation turn out to be, in many cases, more indicative of cancer – and cancer type – than mutations are. The new test zeroes in on portions of the genome where abnormal methylation patterns are found in cancer cells.

“Our previous work indicated that methylation-based assays outperform traditional DNA-sequencing approaches to detecting multiple forms of cancer in blood samples,” said the study’s lead author, Geoffrey Oxnard, MD, of Dana-Farber. “The results of the new study demonstrate that such assays are a feasible way of screening people for cancer.”

In the study, investigators analysed cell-free DNA (DNA that had once been confined to cells but had entered the bloodstream upon the cells’ death) in 3,583 blood samples, including 1,530 from patients diagnosed with cancer and 2,053 from people without cancer. The patient samples comprised more than 20 types of cancer, including hormone receptor-negative breast, colorectal, esophageal, gallbladder, gastric, head and neck, lung, lymphoid leukemia, multiple myeloma, ovarian, and pancreatic cancer.

The overall specificity was 99.4%, meaning only 0.6% of the results incorrectly indicated that cancer was present. The sensitivity of the assay for detecting a pre-specified high mortality cancers (the percent of blood samples from these patients that tested positive for cancer) was 76%. Within this group, the sensitivity was 32% for patients with stage I cancer; 76% for those with stage II; 85% for stage III; and 93% for stage IV. Sensitivity across all cancer types was 55%, with similar increases in detection by stage. For the 97% of samples that returned a tissue of origin result, the test correctly identified the organ or tissue of origin in 89% of cases.

Detecting even a modest percent of common cancers early could translate into many patients who may be able to receive more effective treatment if the test were in wide use, Oxnard remarked.

Dana-Farber Cancer Institutewww.dana-farber.org/newsroom/news-releases/2019/new-blood-test-capable-of-detecting-multiple-types-of-cancer/

A new type of blood test for breast cancer could help avoid thousands of unnecessary surgeries and otherwise precisely monitor disease progression, according to a study led by the Translational Genomics Research Institute (TGen) and Mayo Clinic in Arizona.

The study suggests that the test called TARDIS — TARgeted DIgital Sequencing — is as much as 100 times more sensitive than other blood-based cancer monitoring tests.

TARDIS is a “liquid biopsy” that specifically identifies and quantifies small fragments of cancer DNA circulating in the patient’s bloodstream, known as circulating tumour DNA (ctDNA). According to the study, TARDIS detected ctDNA in as low as 2 parts per 100,000 in patient blood.
“By precisely measuring ctDNA, this test can detect the presence of residual cancer, and inform physicians if cancer has been successfully eradicated by treatment,” said Muhammed Murtaza, M.B.B.S., Ph.D., Assistant Professor and Co-Director of TGen’s Center for Noninvasive Diagnostics. He also holds a joint appointment on the Research Faculty at Mayo Clinic in Arizona, and is one of the study’s senior authors.

For example, Dr. Murtaza explained, TARDIS is precise enough to tell if early stage breast cancer patients have responded well to pre-operative drug therapy. It is more sensitive than the current method of determining response to drug therapy using imaging.

“This has enormous implications for women with breast cancer. This test could help plan the timing and extent of surgical resection and radiation therapy after patients have received pre-operative therapy,” said Dr. Barbara A. Pockaj, M.D., a surgical oncologist who specializes in breast and melanoma cancer patients at Mayo Clinic in Arizona, and is the study’s other senior author. Dr. Pockaj is the Michael M. Eisenberg professor of surgery and the chair of the Breast Cancer Interest Group (BIG), a collaboration between researchers at Mayo, TGen and ASU.

Unlike traditional biopsies, which only produce results from one place at one time, liquid biopsies use a simple blood draw, and so could safely be performed repeatedly, as often as needed, to detect a patient’s disease status.

“TARDIS is a game changer for response monitoring and residual disease detection in early breast cancer treated with curative intent. The sensitivity and specificity of patient-specific TARDIS panels will allow us to tell very early, probably after one cycle, whether neo-adjuvant (before surgery) therapy is working and will also enable detecting micro-metastatic disease and risk-adapted treatment after completing neo-adjuvant therapy,” said Dr. Caldas, who also is Senior Group Leader at the Cancer Research UK Cambridge Institute, and one of the study’s contributing authors.

Following further clinical testing and trials, TARDIS could someday be routinely used for monitoring patients during cancer treatment, and discovering when patients are essentially cured and cancer free.

“The results of these tests could be used to individualize cancer therapy avoiding overtreatment in some cases and under treatment in others,” Dr. Murtaza said. “The central premise of our research is whether we can develop a blood test that can tell patients who have been completely cured apart from patients who have residual disease. We wondered whether we can see clearance of ctDNA from blood in patients who respond well to pre-surgical treatment.”

Current tests and imaging lack the sensitivity needed to make this determination.

“Fragments of ctDNA shed into blood by tumours carry the same cancer-specific mutations as the tumour cells, giving us a way to measure the tumour,” said Bradon McDonald, a computational scientist in Dr. Murtaza’s lab, and the study’s first author.

“The problem is that ctDNA levels can be so low in non-metastatic cancer patients, there are often just not enough fragments of ctDNA in a single blood sample to reliably detect any one mutation. This is especially true in the residual disease setting, when there is no obvious tumour left during or after treatment,” McDonald said. “So, instead of focusing on a single mutation from every patient, we decided to integrate the results of dozens of mutations from each patient.”
Translational Genomics Research Institutewww.tgen.org/news/2019/august/07/new-ctdna-blood-test-for-cancer/