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Unprecedented Analyses of More Than 2,600 Whole Genome Sequences from 38 Different Tumor Types Results in 21 Studies Published Simultaneously in Nature Journals; One Suggests Many Cancer Mutations Occur Years Before the Cancer Develops

In a virtually unprecedented event, 21 open-access research papers arising from the monumental efforts of the ICGC/TCGA consortium on whole genome sequencing and integrative analysis of cancer have been published simultaneously online on February 5, 2020, in the following journals published by Nature: Nature Communications (8), Nature (6), Nature Genetics (5), Nature Biotechnology (1), and Communications Biology (1). The work is based on an international collaboration of over 1,300 scientists and clinicians from 37 countries known as the Pan-Cancer Analysis of Whole Genomes (PCAWG). The effort involved analysis of more than 2,600 genomes of 38 different tumor types, creating a huge resource of primary cancer genomes. The flagship paper is titled “Pan-Cancer Analysis of Whole Genomes.” In this BioQuick post, another one of the 21 articles (“The Evolutionary History of 2,658 Cancers”) is described. The the titles and links for all 21 articles are provided following description of the Evolutionary History article. In addition, related articles, including editorials and a News & Views article are provided at the end. Researchers at EMBL's European Bioinformatics Institute (EMBL-EBI) and the Francis Crick Institute in the UK have analyzed the whole genomes of over 2r,600 tumors from 38 different cancer types to determine the chronology of genomic changes during cancer development. Cancer occurs as part of a lifelong process in which our genome changes over time. As we age, our cells cannot maintain the integrity of the genome after cell division without making some errors (mutations). This process can be accelerated by various genetic predispositions and environmental factors, such as smoking. Over our lifetimes, these mutations build up and cells may be mis-programmed, leading to cancer.

New Route Developed for Synthesis of Deadly Mushroom Toxin Amanitin, Which Is Potentially Useful Therapeutically; Method May Allow Toxin to Be Produced at Industrial Scale, Thus Enabling Possibly Rapid Research Advances

The death cap mushroom (Amanita phalloides) is highly toxic. However, some of its toxins can also be healing when used appropriately: for instance, amanitins are potential components for antibody-based cancer treatments. In the journal Angewandte Chemie, German, in an article published online on December 17, 2019, scientists have now described a new synthetic route for α-amanitin. The open-access article is titled “A Convergent Total Synthesis of the Death Cap Toxin α‐Amanitin.” Their method seems suitable for production on a larger scale, finally making enough of the toxin available for further research. Amanitins inhibit the enzyme RNA polymerase II with high selectivity, which leads to cell death. When transported into tumor cells by antibodies, the toxin could fight tumors. Until recently, however, the only source of amanitins was the mushrooms (Amanita phalloides) themselves, which limited the possibilities for experimentation. Some time ago, a total synthesis was reported for α-amanitin, the most powerful amanitin. Researchers working with Roderich D. Süssmuth, PhD, at the Technical University of Berlin have now introduced an alternative route for a total synthesis that occurs entirely in the liquid phase, allows for the possibility of producing different structural variants, and can be implemented on a larger scale. “We decided to use a convergent route, meaning that several components are first synthesized independently and then finally put together to form the target molecule,” explains Dr. Süssmuth. The building blocks are three peptide fragments made of five, one, and two amino acids. The researchers refer to their method as a [5+1+2] synthesis.

Unlocking the Secrets of Cell Regulation: Researches at University of Bonn Investigate Structure of Long RNAs; Develop New Method to Accurately Measure RNA Lengths

Ribonucleic acids (RNA) ensure that the blueprint in the cell nucleus is translated into vital proteins and that cell functions are regulated. However, little is known about the structure and function of particularly long RNAs, which consist of hundreds or thousands of building blocks. Chemists at the University of Bonn have now developed a new method for this purpose: They mark the complex molecules with tiny "flags" and measure the distances between them with a "molecular ruler". The results are published online on January 25, 2020 in Angewandte Chemie International Edition. The article is titled “EPR Distance Measurements on Long Non-Coding RNAs Empowered by Genetic Alphabet Expansion Transcription.” In living cells, everything follows a plan: The blueprints for all building and operating materials are stored in the cell nucleus. If, for example, a certain protein is required, the genetic information is read from the DNA and translated into ribonucleic acid (RNA). The RNA transmits the blueprint to the cell's "protein factories", the ribosomes. "However, more than 80 percent of ribonucleic acids are not involved in the production of proteins at all," says Dr. Stephanie Kath-Schorr (photo) from the LIMES Institute at the University of Bonn. This so-called "non-coding" RNA is probably involved in various regulatory processes in the cell. Scientists would like to gain a much better understanding of the control processes that non-coding RNA is responsible for. "To do this, however, we must first understand the structures of ribonucleic acids and how they are folded," says Kath-Schorr. The spatial structure seems to have an important role in the function of RNA. It determines which molecules a certain RNA binds to and therefore triggers important processes in the cell.

Scientists Find Long Non-Coding RNA (lncRNA) Affecting Skin Cancer Progression; PRECSIT lncRNA Promotes Growth & Spread of Cutaneous Squamous Cell Carcinoma

Researchers at the University of Turku, Turku University Central Hospital, and Western Cancer Center (FICAN West) have discovered a newly identified long non-coding (lnc) RNA molecule (PRECSIT) that regulates the growth and invasion of squamous cell carcinoma of the skin. In the future, PRECSIT lnc RNA could potentially serve as a new marker for the detection of rapidly advancing or spreading squamous cell carcinoma and as a target for new therapies. Skin cancers are the most common cancers in the world and their incidence is increasing. Squamous cell carcinoma is the most common metastatic skin cancer and its incidence is increasing worldwide. Long-term exposure to the sun's ultraviolet radiation is the most important risk factor for the development of this type of cancer. Squamous cell carcinoma of the skin is characterized by a significant gene mutation burden of cancer cells resulting from long-term exposure to the sun's ultraviolet radiation. Several gene mutations predisposing to skin cancer are known, but the importance of non-coding RNA molecules of the so-called dark side of the genome in the development of squamous cell carcinoma is still unclear, says Professor Veli-Matti Kähäri, MD, PhD, from the Department of Dermatology at the University of Turku in Finland. The majority of the human genome contains genes that do not produce protein, but their role as regulators of cellular functions is still essential. Long non-coding RNAs (lncRNAs) are a largely unknown set of RNAs and recent studies have found that they play a role in regulating signaling pathways, particularly in cancer, says researcher Minna Piipponen, PhD, one of the authors of the study. Thus, RNA molecules could be utilized in cancer diagnostics as specific marker molecules and as targets for new therapies.

11th Annual Precision Medicine World Conference (PMWC 2020) Opens with Awards Ceremony at Genentech Hall, UCSF Mission Bay; Awards Given to Three Major Contributors to Advance of Precision Medicine—Philip Greenberg, Laura van’t Veer, & Brook Byers

The Precision Medicine World Conference (PMWC 2020) opened its eleventh annual meeting ("How Do We Accelerate Precision Medicine and Deliver on Its Promises?”) centered in Silicon Valley on Tuesday evening, January 21, with an awards ceremony at Genentech Hall at UCSF Mission Bay in South San Francisco. (Editor’s Note: Including smaller regional meetings, the PMWC has organized 17 precision medicine meetings in total, since its inaugural Silicon Valley conference in 2009). UCSF was one of three co-hosts of this conference. The other hosts were Stanford Health and the Institute for Precision Medicine, a partnership of the University of Pittsburgh and the University of Pittsburgh Medical Center. The Awards ceremony honored three distinguished contributors to the advance of precision medicine. The MC of the PMWC Awards ceremony was Keith Yamamoto, PhD, Chancellor for Research, Executive Vice Dean of the School of Medicine, and Professor of Cellular and Molecular Pharmacology at UCSF. PMWC Luminary Awards were presented to Philip Greenberg (photo here, see additional event photos at end), MD, Head, Program in Immunology, Fred Hutchinson Cancer Research Center; Professor of Medicine and Immunology, University of Washington; and Member, Parker Institute for Cancer Immunology; and to Laura J. van’t Veer, PhD., Inventor, MammaPrint; Professor of Laboratory Medicine, and Director, Applied Genomics, UCSF Helen Diller Family Comprehensive Cancer Center. The PMWC Luminary Award recognizes individuals who have made significant contributions to accelerate personalized medicine within the clinical setting. Dr. Greenberg received his Luminary Award for “discoveries that led to adoptive immunotherapy with genetically engineered T cells.” Dr.

Developing Brain Is Key Regulator of Innate Immunity in Embryo; Brain Somehow “Senses” Bacterial Pathogens and Sends Signals to Immune Cells Directing Them to Site of Infection

Researchers led by biologists at Tufts University in Boston have discovered that the brains of developing embryos provide signals to a nascent immune system that help it ward off infections and significantly improve the embryo's ability to survive a bacterial challenge. Using frog embryos, which continue to develop with their brains removed, the researchers found that embryos without a brain are not able to marshal the forces of immune cells to an injury or infection site, leading the embryo to succumb to an infection more quickly. By contrast, the presence of a brain crucially helps direct immune cells to the site of injury to overcome the bacterial threat. The study was published online on February 4, 2020 in NPJ Regenerative Medicine. The open-access article is titled “An In Vivo Brain-Bacteria Interface: The Developing Brain As a Key Regulator of Innate Immunity." In a developing embryo, both brain and immune system are not fully formed. The immune system, for its part, consists mostly of an "innate" system of cells that respond immediately to infection and do not require training or produce antibodies. Nevertheless, these cells require signals that prompt them to move toward an infection site and trigger a response. The research team found that the brain appears to contribute to the signals that guide the nascent immune system. When brainless frog embryos were infected with E. coli, only about 16% of embryos survived, while the presence of a brain protected more than 50% from the infection. By following markers of immune cells, researchers confirmed that the effect is not due to the missing brain somehow hampering immune system development because the composition of the immune cells remained the same with or without a brain.

Laura van’t Veer, Inventor of Agendia’s MammaPrint Breast Cancer Assay, Honored with Luminary Award at Precision Medicine World Conference (PMWC 2020)

Laura van ‘t Veer (photo here, also see more photos at end), PhD, Co-Founder of Agendia Inc. and developer of MammaPrint, the 70-gene risk of recurrence assay for breast cancer patients, was recognized by the Precision Medicine World Conference (PMWC) with the PMWC Luminary Award on January 21, 2020. This award recognizes individuals who have made significant contributions to accelerate personalized medicine within the clinical setting. As a Professor of Laboratory Medicine and Director of Applied Genomics at the University California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, Dr. van ‘t Veer is committed to translational medicine that aims to leverage the genomic makeup of patient tumors and improve their clinical outcomes. Dr. van ‘t Veer has authored more than 280 peer-reviewed scientific articles and is a co-inventor on 6 patents. In 2007, she received the European Society of Medical Oncology (ESMO) life-time achievement award for translational research in breast cancer, in 2014 the European Union Women Innovator Award, and in 2015 the EPO European Inventor award. In 2019, she was recognized by 24/7 Wall Street as one of “32 Amazing Women Inventors.” Currently, Dr. van ‘t Veer serves as the Biomarker Committee Chair for the Quantum Leap Healthcare Collaborative (QLHC)-sponsored I-SPY 2 adaptive clinical trial. By using genomic information obtained from participating patients, this trial seeks to elucidate how different tumors will respond to novel drug regimens, thus improving patient outcomes. At the PMWC Awards Reception, Dr. van’t Veer was introduced by Agendia CEO Mark Straley. Tal Bahar Co-Founder and President, PMWC commented, “We are delighted to have Dr.

Recurrent Mutations in Splicing Factor (SRSF2) Gene Cause Excessive Nonsense-Mediated Decay (NMD) and May Cause Many Different Blood Cancers

A genetic mutation that disrupts how DNA sends messages to the rest of a cell has been linked to a large number of blood cancers. Thanks to a collaboration between biologists at Cold Spring Harbor Laboratory (CSHL) and an oncologist at Memorial Sloan Kettering Cancer Center (MSKCC), we now know how the mutation triggers a chain of biological events that lead to most leukemias. The deadly chain of events begins with RNA splicing, a process that converts messages from DNA into instructions for making proteins in a cell. Errors in RNA splicing can result in poorly formed proteins that are unable to do their job. The CSHL-MSKCC team found that in blood cancers, a process associated with splicing called nonsense-mediated mRNA decay (NMD) is excessively active. After splicing converts DNA messages, the NMD process normally serves as "quality control," destroying messages that contain mistakes before a broken protein is made. The laboratory of Adrian Kraimer (photo), PhD, at CSHL determined that when the gene called SRSF2 is mutated, NMD destroys many more messages, including some that have not been likely targets of NMD before. Messages that are important for healthy blood cell production are one of these new targets. The result of excessively active NMD is less healthy blood cells and more sickly or immature cells--a hallmark of blood cancer. "RNA splicing factor mutations are seen in virtually all forms of leukemia, both chronic as well as acute myeloid leukemias and also even chronic lymphocytic leukemia," said Omar Abdel-Wahab, MD, at MSKCC. "I'm a hematological oncologist--I think a lot about blood cancer--so this caught my attention right away." Scientists have seen other cancers manipulate NMD into protecting solid tumors.

Penn Doctor Chases Cure for His Own Rare Disease (Castleman Disease); One in Ten Have a Rare Diseae (Over 7,000 Rare Diseases), But for 95% of These Diseases, There Is Not a Single FDA-Approved Drug

In the introduction to his memoir “Chasing My Cure: A Doctor’s Race to Turn Hope Into Action (https://chasingmycure.com/), Dr. David Fajgenbaum discussed how he learned that “hope cannot be a passive concept.” “It’s a choice and a force,” he wrote. “Hoping for something takes more than casting out a wish to the universe and waiting for it to occur. Hope should inspire action. And when it does inspire action in medicine and science, that hope can become a reality, beyond your wildest dreams.” Hope is something Dr. Fajgenbaum, 34, an Assistant Professor of Medicine at The Perelman School Of Medicine at the University of Pennsylvania, knows Intimately. He’s been in hospital rooms as a patient and a doctor — seeing both sides of what it’s like to diagnose and be diagnosed with a deadly disease. He knows what it’s like to experience radical ups and downs in his own health and see others go through the same thing. His life changed in 2010 while he was a third-year medical student at the same university where he now works. He began noticing strange, sudden shifts in his health — from night sweats to fatigue. Within several weeks, his organs were failing, and in November of that year, he was read his last rites. What was wrong? Dr. Fajgenbaum received a very rare diagnosis: Castleman disease (https://www.healthline.com/health/castleman-disease), an immune disorder that results in an overgrowth of cells in the lymph nodes. While not a form of cancer, the condition is often initially confused with a cancer diagnosis. The lymph nodes generally tied to the condition are those found in the neck, underarm, groin, and collarbone. For Dr.

Researchers Identify Possible New Combination Treatment for Advanced Melanoma

A study by researchers at the UCLA Jonsson Comprehensive Cancer Center and coleagues suggests that using an immunotherapy drug called NKTR-214, also known as bempegaldesleukin, in combination with an infusion of anti-tumor immune cells (T cells), may produce a stronger immune response that could help fight advanced melanoma. When tested in mice with melanoma tumors that were unlikely to stimulate an immune response, the approach increased the number of anti-tumor immune cells, and those immune cells lived longer and functioned better than the standard therapy, empowering the cells to destroy the tumor. Adoptive cell therapy is a type of immunotherapy that has had promising results for treating people with advanced cancers. The approach involves extracting and harvesting immune cells from a patient and engineering them in the laboratory to attack specific antigens on the surface of tumors. One challenge is that it requires giving patients interleukin 2, a protein signaling molecule in the immune system, to promote the development and expansion of the infused immune cells. But interleukin 2 can also activate cells to suppress the immune system, and because it is highly toxic, it can have serious adverse side effects. Researchers have been seeking ways to produce large number of immune cells without exposing patients to those negative side effects — including by combining adoptive cell therapy with other treatments. In this study, researchers used mice to test NKTR-214 in combination with adoptive cell therapy. Using bioluminescence imaging, the researchers tracked the movement of T cells in the mice that received the combination therapy. The team observed an expansion of T cells in the spleen, the organ that helps accelerate the activation and expansion of T cells throughout the body.

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