“Polygenic Adaptation”
China’s health ministry has issued draft regulations that will restrict the use of gene editing in humans, just three months after Chinese researcher He Jiankui announced that twin girls had been born with edited genomes. The proposal includes severe penalties for those who break the rules. If approved, scientists say the policy could have gains and drawbacks for research.
Blood tumor mutational burden may give insight into which patients with non-small cell lung cancer (NSCLC) may benefit from therapy with anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibodies, according to Chinese researchers.
A considerable number of patients with advanced cancer may not be able to provide sufficient tissue for molecular testing to guide treatment decisions, Dr. Jie Wang of Peking Union Medical College and colleagues note in JAMA Oncology, online February 28. However, rather than use tumor mutational burden measured by whole-exome sequencing or cancer gene panel, the researchers sought to determine the utility of using circulating tumor DNA in blood.
Lupus can be a stubborn disease to treat. Although many struck by the autoimmune condition live relatively normal lives, some suffer from kidney failure, blood clots, and other complications that can be deadly. Now, scientists have found that a novel treatment that wipes out the immune system’s B cells cures mice of the condition. Though the work is preliminary, it has excited researchers because it uses a therapy already approved for people with blood cancer.
The strategy is known as chimeric antigen receptor (CAR)-T therapy.
Chimeric antigen receptor (CAR) T cells are about as cutting-edge as cancer care gets today. Having demonstrated the ability to eradicate tumor cells in up to 90% of patients with certain blood cancers, these engineered immune cells became the first class of gene therapy to win FDA approval in 2017—with Novartis’ Kymriah getting the nod in August, followed by Kite Therapeutics’ Yescarta in October.3 But Alexander Marson, MD, PhD, knows these sophisticated cells are capable of so much more.
Marson, an immunologist at the University of California at San Francisco, is exploring this potential by using the CRISPR-Cas9 system to introduce precisely targeted genome modifications. The idea is that by adding or deleting specific genomic sequences, one can make these cells more lethal for tumors but also safer for the patient. Marson’s team recently developed a platform called SLICE4—single-guide RNA (sgRNA) lentiviral infection with Cas9 protein electroporation—to perform diverse CRISPR modifications in many cells in parallel, in hopes of rapidly identifying changes that measurably improve CAR T-cell performance. “We’re pretty good at manufacturing the ‘hardware’ of gene edited cells, and we’re continuing to improve that,” says Marson. “The really interesting thing will be what genetic ‘software’ we can put into them.”
Mutations in the dystrophin gene cause Duchenne muscular dystrophy (DMD), which is characterized by lethal degeneration of cardiac and skeletal muscles. Mutations that delete exon 44 of the dystrophin gene represent one of the most common causes of DMD and can be corrected in ~12% of patients by editing surrounding exons, which restores the dystrophin open reading frame. Here, we present a simple and efficient strategy for correction of exon 44 deletion mutations by CRISPR-Cas9 gene editing in cardiomyocytes obtained from patient-derived induced pluripotent stem cells and in a new mouse model harboring the same deletion mutation. Using AAV9 encoding Cas9 and single guide RNAs, we also demonstrate the importance of the dosages of these gene editing components for optimal gene correction in vivo. Our findings represent a significant step toward possible clinical application of gene editing for correction of DMD.
This Ovarian Cancer Awareness Month our Cancer Stories Officer, Lydia Brain, spoke to Davina Gardner – a survivor of ovarian and breast cancer – about being a BRCA2 gene carrier and how it has affected her and her family.
Summary
Using genetically engineered mouse models and high-throughput screening technologies, MSK researchers have found a surprising new approach for targeting glioblastoma.
The type of brain tumor known as glioblastoma (GBM) is one of the most difficult cancers to treat. Complete removal by surgery is impossible because of where and how they infiltrate brain tissue. Additionally, the most commonly used treatments for glioblastoma — radiation therapy and the chemotherapy drug temozolomide (Temodar®) — are not very effective over the long term.
Researchers in Memorial Sloan Kettering’s Brain Tumor Center, led by developmental biologist Luis F. Parada, are focused on finding more effective ways of attacking this deadly cancer. In a study published in Nature, they report on the identification of a compound that kills glioblastoma cells using a mechanism that’s completely different from earlier treatments. The scientists say one of the keys to finding better drugs is developing models that accurately reflect the cells that make up these tumors.
Positive Screens Warrant Genetic Counseling, Testing
March 06, 2019 03:17 pm Chris Crawford – Mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are just one of many factors that can greatly increase a woman's risk of developing certain cancers, such as breast and ovarian cancer. One important step in preventing these cancers is to help women understand their risk.
On Jan. 15, the U.S. Preventive Services Task Force (USPSTF) posted a draft recommendation statement(www.uspreventiveservicestaskforce.org) and draft evidence review(www.uspreventiveservicestaskforce.org) on risk assessment, genetic counseling and genetic testing for BRCA-related cancer in women.
Based on its review of the evidence, the USPSTF recommended that physicians screen women who have family members with breast, ovarian, tubal or peritoneal cancer or who have an ethnicity or ancestry associated with BRCA1 or BRCA2 gene mutations with one of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in these breast cancer susceptibility genes, the draft recommendation said.
Genetic testing that alerts patients to harmful gene mutations is paving the way to aid in preventing inherited cancers.
Cape Cod natives and sisters Liz Ellis, Katie Paquin and Christine Leary, who were all diagnosed with breast cancer within one year, carry the PALB2 gene, which is found to increase the risk of breast cancer.
Dr. Michael Misialek, associate chair of pathology at Newton-Wellesley Hospital, said knowing about a family history of cancer is the first step in taking preventative measures against the disease and getting tested for harmful genetic mutations.
Researchers have published what may be the validated largest family tree ever: a genealogy database stretching back 5 centuries that links 13 million people related by blood or marriage. The tree has already led to such insights as the link between genes and longevity and why our ancestors married whom they did. And researchers say that’s just a start.
“This study is an impressive and clever use of crowdsourcing data to address a number of interesting scientific questions,” says geneticist Peter Visscher of the University of Queensland in Brisbane, Australia, who was not involved with the work. The tree’s bigger promise, he and others say, could come if it were linked to health information to explore the role of genetics in diseases.
Deep in the cells of the human immune system, DNA is constantly being replicated, transcribed and even mutated — but rarely does it change dramatically. Like every other living organism, humans and their genes developed from millions of years of evolutionary pruning.
But to Yale microbiologists, altering the entire genomes of T-cells — the body’s main offensive weapon against diseases such as cancer — is as simple as putting together a Lego set.
In a new study published in the journal Nature Methods on Feb. 25, researchers at the Sidi Chen Lab at Yale have come up with a new way to use the gene-editing technology CRISPR that significantly improves the technology’s efficiency. By allowing scientists to select multiple genes to include in the same CRISPR system, scientists will now be able to edit their samples’ genomes in one go, saving time and money in the process. These findings have considerable promise for engineering T-cells that can fight off cancers such as leukemia and lymphoma.
For just the second time, a patient with AIDS appears to have been cured of the disease after receiving a stem cell transplant from a donor with a genetic mutation that provides resistance to HIV, which causes AIDS. But the mutation is exceedingly rare, raising controversial questions of whether it may be replicated using nascent gene-editing tools like CRISPR/Cas9.
NEW YORK (GenomeWeb) – Some large structural variants in the human genome exhibit population-specific patterns, according to a new analysis of more than 150 genome maps.
Large structural variants — those that are bigger than 2 kilobases — are difficult to detect, especially as short-read sequencing technologies are the most commonly used tools in genomic analysis.
For their study, Pui-Yan Kwok from the University of California, San Francisco and his colleagues analyzed optical genome maps generated for more than 150 individuals representing more than two dozen populations. A phylogenetic analysis of these maps indicated that some SVs and CNVs show variable population patterns. The researchers were also able to characterize SVs in typically intractable regions of the genome, including spots not covered by the human reference genome. Their results were published yesterday in Nature Communications.
The connection between an influenza virus surface protein and a host cell lipid has been discovered by researchers at the University of Maine and the National Institutes of Health. Confirmation of direct interaction between the protein and lipid could lead to new antiviral therapies.
Despite being globally infrequent, testicular germ cell tumors (TGCTs) represent the most common neoplasms in young adult Caucasian men. They are challenging tumors, hallmarked by striking heterogeneity; however, they show very few mutations and share the same (almost) unifying cytogenetic abnormality, in the form of isochromosome 12p. This leaves room for Epigenetic phenomena to explain such diversity. Epigenetic mechanisms frequently deregulated in various cancer types include DNA methylation, non-coding RNAs, but also the effect on chromatin accessibility subsequent to histone post-translational modifications (PTMs) and to the action of chromatin remodeling complexes (ChRCs). These modifications are introduced by complex families of enzymes (DNA and histone modifying enzymes) which show, naturally, deregulated expression in cancer. However, and despite epigenetic (de)regulation being especially relevant in TGCTs, few studies have addressed the role of these enzymes in this tumor model.
CRISPR-Cas9 genome editing therapy has been shown by the Salk Institute team to suppress the accelerated aging observed in mice with Hutchinson-Gilford Progeria syndrome; and provided insight into the molecular pathways involved in accelerated aging, and how to reduce toxic proteins via gene therapy.
Dante Labs takes the first step of its ambitious project to integrate high coverage genome sequencing in clinical care in clinics and hospitals.
Dante Labs has announced the first of hundreds of European clinics which will integrate whole genome and whole exome sequencing in standard clinical care, further making personalized medicine a standard within the European health care system.
The clinic, "Villa Letizia," is located in L’Aquila, Italy, and is the selected destination for patients across the entire Mediterranean region. Patients will receive 100X whole exome or 30X whole genome sequencing with premium turnaround time and personalized reports as part of their standard clinical care.
Coordinating the sort of full-spectrum analysis more commonly deployed in cancer research, scientists based at Houston Methodist examined flesh-eating strains of Streptococcus pyogenesboth genomically and transcriptomally. Once the scientists had amassed an unusually large data set, they sifted through it with artificial intelligence tools and discovered a novel virulence mechanism. In addition to explaining how a run-of-the-mill strep infection can turn into a devastating flesh-eating disease, the mechanism may guide efforts to develop vaccines and therapies.
Comprehensive clinical genomic testing of an adolescent patient, including whole genome sequencing, helped researchers identify mutations in a single gene that drive the most common childhood melanoma. The St. Jude Children's Research Hospital study appears as an advance online publication today in the journal Nature Medicine.
Healthy people in the UK are to be controversially offered genetic testing by the National Health Service (NHS) – for a fee. The plan has stoked concerns among geneticists and clinicians, who question its clinical usefulness for healthy people and worry it could waste NHS resources.
UK health minister Matthew Hancock said seriously ill children and adults with genetic conditions will be offered the service for free, but healthy people will pay and have the option of having their DNA analysed by NHS scientists. This will help predict a patient’s risk of developing various conditions, he said.
