Breaking News
May 3, 2019 - Vaping and Smoking May Signal Greater Motivation to Quit
May 3, 2019 - Dementia looks different in brains of Hispanics
May 3, 2019 - Short-Staffed Nursing Homes See Drop In Medicare Ratings
May 3, 2019 - Study of teens with eating disorders explores how substance users differ from non-substance users
May 3, 2019 - Scientists develop new video game that may help in the study of Alzheimer’s
May 3, 2019 - Arc Bio introduces Galileo Pathogen Solution product line at ASM Clinical Virology Symposium
May 3, 2019 - Cornell University study uncovers relationship between starch digestion gene and gut bacteria
May 3, 2019 - How to Safely Use Glucose Meters and Test Strips for Diabetes
May 3, 2019 - Anti-inflammatory drugs ineffective for prevention of Alzheimer’s disease
May 3, 2019 - Study tracks Pennsylvania’s oil and gas waste-disposal practices
May 3, 2019 - Creating a better radiation diagnostic test for astronauts
May 3, 2019 - Vegans are often deficient in these four nutrients
May 3, 2019 - PPDC announces seed grants to develop medical devices for children
May 3, 2019 - Study maps out the frequency and impact of water polo head injuries
May 3, 2019 - Research on Reddit identifies risks associated with unproven treatments for opioid addiction
May 3, 2019 - Good smells may help ease tobacco cravings
May 3, 2019 - Medical financial hardship found to be very common among people in the United States
May 3, 2019 - Researchers develop multimodal system for personalized post-stroke rehabilitation
May 3, 2019 - Study shows significant mortality benefit with CABG over percutaneous coronary intervention
May 3, 2019 - Will gene-editing of human embryos ever be justifiable?
May 3, 2019 - FDA Approves Dengvaxia (dengue vaccine) for the Prevention of Dengue Disease in Endemic Regions
May 3, 2019 - Why Tonsillitis Keeps Coming Back
May 3, 2019 - Fighting the opioid epidemic with data
May 3, 2019 - Maggot sausages may soon be a reality
May 3, 2019 - Deletion of ATDC gene prevents development of pancreatic cancer in mice
May 2, 2019 - Targeted Therapy Promising for Rare Hematologic Cancer
May 2, 2019 - Alzheimer’s disease is a ‘double-prion disorder,’ study shows
May 2, 2019 - Reservoir bugs: How one bacterial menace makes its home in the human stomach
May 2, 2019 - Clinical, Admin Staff From Cardiology Get Sneak Peek at Epic
May 2, 2019 - Depression increases hospital use and mortality in children
May 2, 2019 - Vicon and NOC support CURE International to create first gait lab in Ethiopia
May 2, 2019 - Researchers use 3D printer to make paper organs
May 2, 2019 - Viral infection in utero associated with behavioral abnormalities in offspring
May 2, 2019 - U.S. Teen Opioid Deaths Soaring
May 2, 2019 - Opioid distribution data should be public
May 2, 2019 - In the Spotlight: “I’m learning every single day”
May 2, 2019 - 2019 Schaefer Scholars Announced
May 2, 2019 - Podcast: KHN’s ‘What The Health?’ Bye-Bye, ACA, And Hello ‘Medicare-For-All’?
May 2, 2019 - Study describes new viral molecular evasion mechanism used by cytomegalovirus
May 2, 2019 - SLU study suggests a more equitable way for Medicare reimbursement
May 2, 2019 - Scientists discover first gene involved in lower urinary tract obstruction
May 2, 2019 - Researchers identify 34 genes associated with increased risk of ovarian cancer
May 2, 2019 - Many low-income infants receive formula in the first few days of life, finds study
May 2, 2019 - Global study finds high success rate for hip and knee replacements
May 2, 2019 - Taking depression seriously: What is it?
May 2, 2019 - With Head Injuries Mounting, Will Cities Put Their Feet Down On E-Scooters?
May 2, 2019 - Scientists develop small fluorophores for tracking metabolites in living cells
May 2, 2019 - Study casts new light into how mothers’ and babies’ genes influence birth weight
May 2, 2019 - Researchers uncover new brain mechanisms regulating body weight
May 2, 2019 - Organ-on-chip systems offered to Asia-Pacific regions by Sydney’s AXT
May 2, 2019 - Adoption of new rules drops readmission penalties against safety net hospitals
May 2, 2019 - Kids and teens who consume zero-calorie sweetened beverages do not save calories
May 2, 2019 - Improved procedure for cancer-related erectile dysfunction
May 2, 2019 - Hormone may improve social behavior in autism
May 2, 2019 - Alzheimer’s disease may be caused by infectious proteins called prions
May 2, 2019 - Even Doctors Can’t Navigate Our ‘Broken Health Care System’
May 2, 2019 - Study looks at the impact on criminal persistence of head injuries
May 2, 2019 - Honey ‘as high in sugars as table sugar’
May 2, 2019 - Innovations to U.S. food system could help consumers in choosing healthy foods
May 2, 2019 - FDA Approves Mavyret (glecaprevir and pibrentasvir) as First Treatment for All Genotypes of Hepatitis C in Pediatric Patients
May 2, 2019 - Women underreport prevalence and intensity of their own snoring
May 2, 2019 - Concussion summit focuses on science behind brain injury
May 2, 2019 - Booker’s Argument For Environmental Justice Stays Within The Lines
May 2, 2019 - Cornell research explains increased metastatic cancer risk in diabetics
May 2, 2019 - Mount Sinai study provides fresh insights into cellular pathways that cause cancer
May 2, 2019 - Researchers to study link between prenatal pesticide exposures and childhood ADHD
May 2, 2019 - CoGEN Congress 2019: Speakers’ overviews
May 2, 2019 - A new strategy for managing diabetic macular edema in people with good vision
May 2, 2019 - Sagent Pharmaceuticals Issues Voluntary Nationwide Recall of Ketorolac Tromethamine Injection, USP, 60mg/2mL (30mg per mL) Due to Lack of Sterility Assurance
May 2, 2019 - Screen time associated with behavioral problems in preschoolers
May 2, 2019 - Hormone reduces social impairment in kids with autism | News Center
May 2, 2019 - Researchers synthesize peroxidase-mimicking nanozyme with low cost and superior catalytic activity
May 2, 2019 - Study results of a potential drug to treat Type 2 diabetes in children announced
May 2, 2019 - Multigene test helps doctors to make effective treatment decisions for breast cancer patients
May 2, 2019 - UNC School of Medicine initiative providing unique care to dementia patients
May 2, 2019 - Nestlé Health Science and VHP join forces to launch innovative COPES program for cancer patients
May 2, 2019 - Study examines how our brain generates consciousness and loses it during anesthesia
May 2, 2019 - Transition Support Program May Aid Young Adults With Type 1 Diabetes
May 2, 2019 - Study shows how neutrophils exacerbate atherosclerosis by inducing smooth muscle-cell death
May 2, 2019 - Research reveals complexity of how we make decisions
Thousands of breast cancer gene variants engineered and analyzed

Thousands of breast cancer gene variants engineered and analyzed

Greg Findlay talks about saturation genome editing of BRCA1 at his thesis defense at the University of Washington School of Medicine. He is an M.D./Ph.D. student at the school. Credit: UW Department of Genome Sciences

A new scientific analysis of nearly 4,000 mutations deliberately engineered into the BRCA1 gene will immediately benefit people undergoing genetic testing for breast or ovarian cancer risk.

The study will be published in the Sept. 12 edition of the scientific journal, Nature. Additional data from the research has been made available online.

Jay Shendure and Lea Starita, faculty in the Department of Genome Sciences at the University of Washington School of Medicine, are the senior authors. Shendure directs the Brotman Baty Institute for Precision Medicine in Seattle, which helped support the study. Starita co-directs the Brotman Baty Advanced Technology Lab. Shendure is also a Howard Hughes Medical Institute investigator.

Greg Findlay, an M.D./Ph.D. student in the physician-scientist training program at the UW medical school, led the study, which is entitled, “Accurate classification of BRCA1 variants with saturation genome editing.”

The BRCA1 gene suppresses tumors, but the exact mechanisms by which is does this are not fully understood. Certain mutations in the gene are known to predispose women to breast and ovarian cancers. If a healthy woman undergoes genetic testing and a cancer-predisposing mutation is found, surgery or more frequent screening can greatly reduce her risk of ever getting those types of cancer.

However, many women undergoing genetic screening for breast and ovarian cancer learn that their BRCA1 gene contains a variant of uncertain significance. This is a mutation that is not currently known to cause cancer, but that theoretically could. BRCA1 is an exceptionally well-studied gene, but at present thousands of mutations in it fall into this category. Their implications for cancer risk are unknown.

“For example,” Shendure said, “I might sequence the BRCA1 gene in a woman and observe that she has a mutation, but I don’t know whether that mutation will actually lead to an increased risk of breast cancer or whether it will be perfectly harmless.”

These variants of uncertain significance, the scientists wrote in their report, fundamentally limit the clinical utility of a patient’s genetic information. There is a concern, Findlay said, that women who harbor variants that indeed lead to cancer are not identified during genetic testing, and therefore are not presented with options that might allow them to avoid breast cancer or detect it in its more treatable stages.

The BRCA1 gene has been sequenced in millions of women in the United States alone over the past decade. The idea that mutations in a gene could account for some cases of breast cancer, as well as the mapping of the BRCA1 gene’s location on chromosome 17, was proposed in 1990 by geneticist and epidemiologist Mary-Clare King, after reviewing breast cancer inheritance patterns in families. King joined the UW medical school faculty in 1995.

“Frequently women are being tested for BRCA1 mutations because they have a family history of breast or ovarian cancer,” Starita said. “To be told that they have a genetic variant in this cancer predisposing gene, but that the doctor doesn’t know what it means, does not reduce their stress or their anxiety.”

Dr. Jay Shendure and Dr. Lea Starita at the University of Washington Department of Genome Sciences and the Brotman Baty Institute for Precision Medicine talk about the findings from engineering mutations into the breast cancer gene BRCA1, analyzing their effects in living cells in the lab, and what the findings might mean for people who have received previously inconclusive results from testing of that gene. Credit: UW Medicine

“The challenge with BRCA1 testing, and with genetic testing more generally, is even though the cost of genome sequencing has plummeted, we continue to have trouble interpreting what that information means,” Shendure said.

“The premise of precision medicine that we’ve been promising for 10 or 15 years now is that we’ll sequence the genomes of ordinary citizens, and that information will improve their health outcomes. We hope this new study brings us one step closer to delivering on that promise.”

To help clinicians and patients obtain better information about genetic variants, Findlay developed a research approach called ‘saturation genome editing’. This method relies on CRISPR, an enzyme tool that cuts strands of DNA to modify its sequence. With it, they made thousands of miniscule revisions in the BRCA1 gene, even changes that have not yet been seen in a human. Then the scientists measured the effects of each mutation to see which ones caused problems in human cells growing in a dish.

“Being able to break it down at the level of single base pairs of DNA was pretty exciting,” the researchers said. “We found that you can study changes in the BRCA1 gene in the lab, and they reflect with surprising accuracy what happens in a person with that variant. Even though we’re working with cells in a dish, when we put changes into the genomes of those cells, and look at the places where the right answers should be, they almost always line up with what we observe in patients.”

Previously only a few different mutations could be examined at a time. Now, the means to edit a gene into myriad versions is making it easier to understand how our DNA functions.

“We are basically categorizing all of the possible changes across critical regions of the BRCA1 gene as either behaving like disease-causing mutations or not,” Findlay said. The researchers needed about six months to test almost 4,000 mutations. They are extending this work to cover the entire BRCA1 gene over the next couple of years.

The researchers are quickly releasing newly available variant information through the Brotman Baty database to assist patients and clinicians trying to figure out what a test result might mean.

“Our hope,” Starita said, “is that this database will continue to grow and will become a central point for guiding the interpretation of actionable variants as they are first observed in women.”

“The ability to study in a dish what will happen in a living, breathing human, at scale, opens up a lot of possibilities in medical genetics,” Shendure added. The scientists plan to apply the saturation genome editing methods to other cancer risk genes.

“The study serves as a blueprint,” Findlay noted, “for how to test rare mutations in important genes that have big consequences for human health.”


Explore further:
Genetic predisposition to breast cancer due to non-brca mutations in ashkenazi Jewish women

More information:
Gregory M. Findlay et al, Accurate classification of BRCA1 variants with saturation genome editing, Nature (2018). DOI: 10.1038/s41586-018-0461-z

Journal reference:
Nature

Provided by:
University of Washington

Tagged with:

About author

Related Articles