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Archive - Aug 15, 2019


Study Identifies Gene Mutation (in RABL3 Gene) Linked to Hereditary Pancreatic Cancer

Pancreatic cancer is one of the deadliest cancers with limited treatment options. It typically comes with an especially poor prognosis due to its lack of symptoms until advanced stages and its ability to resist many anticancer therapies. Identifying genes involved in its development may lead to earlier diagnoses and improved treatments. Now, a research team led by investigators at Massachusetts General Hospital (MGH), Brigham and Women's Hospital, and Dana-Farber Cancer Institute has found that a mutation in a particular gene is associated with hereditary forms of pancreatic cancer in one family studied. Approximately 10% of pancreatic cancer is believed to be hereditary (see discussion of pancreatic cancer in former US President Jimmy Carter's family below). The research group also uncovered a mechanism by which mutations such as the one they identified may contribute to the development of tumors. In their study, which was published online on August 12, 2019 in Nature Genetics, the researchers sequenced the genomes of a family in which multiple members had pancreatic cancer. The analyses revealed a mutation in the RAS oncogene family-like 3 (RABL3) gene. The article is titled “Mutations in RABL3 Alter KRAS Prenylation and Are Associated with Hereditary Pancreatic Cancer.” To assess the effects of this gene mutation, the investigators recapitulated it in zebrafish, a model which offers large populations for studying the impact of newly discovered genetic mutations on cancer risk. The fish carrying the mutation developed cancers at an accelerated rate and with greater frequency. Additional studies revealed that the protein expressed by RABL3 interacts with components of the RAS signaling pathway, which has been implicated in various forms of cancer and other conditions.

Variants in MS4A4A Gene Influence Levels of Soluble TREM2 and Affect Susceptibility to Alzheimer’s Disease; Results Suggest Increased Focus on Brain’s Immune Cells (Microglia)

An international team of researchers led by scientists at Washington University School of Medicine in St. Louis has identified a pair of genes that influence risk for both late-onset and early-onset Alzheimer's disease. Most genes implicated thus far in Alzheimer's affect neurons that transmit messages, allowing different regions of the brain to communicate with one another. But the newly identified genes affect an entirely different population of cells: the brain's immune cells. The findings, published online on August 14, 2019 in Science Translational Medicine, could provide scientists with new targets and a strategy for delaying the onset of Alzheimer's symptoms. The article is titled “The MS4A Gene Cluster Is a Key Modulator of Soluble TREM2 and Alzheimer’s Disease Risk.” The identified genes -- known as MS4A4A and TREM2 -- operate in the microglia (image), the brain's immune cells. The genes influence Alzheimer's risk by altering levels of TREM2, a protein that is believed to help microglia cells clear excessive amounts of the Alzheimer's proteins beta-amyloid and tau from the brain. "The findings point to a new therapeutic strategy," said co-senior investigator Carlos Cruchaga, PhD, a Professor of Psychiatry and Director of the NeuroGenomics and Informatics Group at Washington University School of Medicine. "If we can do something to raise levels of the TREM2 protein in the cerebrospinal fluid, we may be able to protect against Alzheimer's disease or slow its development." In this study, the researchers measured soluble TREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were ages 55 to 90. Of those subjects, 172 had Alzheimer's disease, 169 were cognitively normal, and another 183 had early mild cognitive impairment.

Lost in Translation: Researchers Discover Surprising Amount of Variation in tRNA Genes; Suggest Possible Role in Disease

A molecule called transfer ribonucleic acid (tRNA), is an essential component of the human genome that acts as a translator. It reads the genetic code and translates it into proteins - one of the key building blocks of the human body. When researchers and clinicians investigate the genome's relation to disease, they have traditionally focused on mutations in the code for proteins. But now researchers at Western University in Canada have shown that the genes encoding tRNAs can also have mutations that cause the code to be misread, and in greater numbers than previously thought. Think of it like a translator app on your phone - if it has errors in its software, the output is going to be all wrong, even if the original text is correct. The results of the new study were published online on August 13, 2019 in RNA Biology. The article is titled “Targeted Sequencing Reveals Expanded Genetic Diversity of Human Transfer RNAs.” "This actually changes the way we think about the genetic code," said lead author Mathew Berg, a PhD Candidate at Western's Schulich School of Medicine & Dentistry.

Researchers ID Possible Target Matrix Protein (Perlecan) in Effort to Halt Spread of Pancreatic Cancer

An international team of researchers has revealed how aggressive pancreatic cancer cells change their environment to enable easy passage to other parts of the body (metastasis) - the main cause of pancreatic cancer-related death. The researchers discovered that some pancreatic tumors produce more of a molecule called “perlecan” to remodel the environment around them, which helps cancer cells spread more easily to other parts of the body, and also protects them against chemotherapy. In a mouse model, the researchers showed that lowering the levels of perlecan reduced the spread of pancreatic cancer and improved response to chemotherapy. Led by Associate Professor Paul Timpson, PhD, Head of the Invasion and Metastasis Laboratory, and Thomas Cox, PhD, Leader of the Matrix and Metastasis Group, both at the Garvan Institute of Medical Research in Australia, the research may provide a promising new path to more effective treatment options for individuals with pancreatic and other cancers. The findings were published online on August 12, 2019 in Nature Communications. The open-access article is titled “CAF Hierarchy Driven by Pancreatic Cancer Cell p53-Status Creates a Pro-Metastatic and Chemoresistant Environment via Perlecan.”"Pancreatic cancer is very aggressive, and, by the time most cases are diagnosed, the tumor is often inoperable," says Associate Professor Timpson. "What we've discovered in this study is a two-pronged approach for treating pancreatic cancer that we believe will improve the efficiency of chemotherapy and may help reduce tumor progression and spread." Pancreatic cancer is one of the most lethal forms of cancer, with a five-year survival of ~9% in Australia.