Results will be immediately useful for many patients with inconclusive genetic test results before – ScienceDaily

The study will be published in the September 12 edition of the scientific journal, Nature. Additional data from the research was posted online.

Jay Shendure and Lea Starita, professors in the Department of Genomic Sciences, University of Washington School of Medicine, are the lead authors. Shendure heads 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 an investigator of the Howard Hughes Medical Institute.

Greg Findlay, a DM / Ph.D. A student in the doctor-researcher training program at the Faculty of Medicine at the University of New York, she led the study titled "Precise Classification of BRCA1 Variants with Saturation Genome Editing". ".

The BRCA1 gene suppresses tumors, but the exact mechanisms by which it does so are not fully understood. Some gene mutations are known to predispose women to breast and ovarian cancers. If a healthy woman undergoes genetic testing and a mutation predisposing to cancer is detected, more frequent surgery or screening can significantly reduce her risk of contracting these types of cancer.

However, many women undergoing genetic testing for breast and ovarian cancer are learning that their BRCA1 gene contains a variant of uncertain significance. This is a mutation that we do not know is currently causing cancer, but that could in theory. BRCA1 is an exceptionally well-studied gene, but currently thousands of mutations fall into this category. Their implications for cancer risk are unknown.

"For example," said Shendure, "I could sequence the BRCA1 gene in a woman and observe that she has a mutation, but I do not know if this mutation will actually lead to an increased risk of breast cancer or if she will be perfectly harmless. "

Scientists have written in their report that these inherently uncertain variants fundamentally limit the clinical utility of a patient's genetic information. According to Findlay, women with variants leading to cancer are not identified in genetic testing and are therefore not presented with options to prevent or detect breast cancer at its most easily diagnosed stages. treat.

The BRCA1 gene has been sequenced in millions of women in the United States alone over the last decade. The idea that mutations in a gene could explain some cases of breast cancer, as well as mapping the localization of the BRCA1 gene on chromosome 17, was proposed in 1990 by Mary-Clare King, a geneticist and epidemiologist. families. King joined UW's faculty of medicine in 1995.

"Frequently, women are screened for mutations in the BRCA1 gene because they have a family history of breast or ovarian cancer," said Mr. Starita. "Be told that they have a genetic variant in this gene predisposing to cancer, but that the doctor does not know what it means, does not reduce their stress or anxiety."

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

"The premise of precision medicine that we have been promising for 10 or 15 years is to sequence the genomes of ordinary people, and this information will improve their health outcomes, and we hope this new study will bring us closer to delivering on that promise."

To help clinicians and patients obtain better information on genetic variants, Findlay has developed a research approach called "saturation genome editing". This method is based on CRISPR, an enzymatic tool that cuts DNA strands to modify its sequence. With that, they made thousands of tiny revisions in the BRCA1 gene, even changes that have not yet been observed in humans. Next, scientists measured the effects of each mutation to see which ones were causing problems in human cells growing in a dish.

"Being able to break it down to the level of single DNA pairs was very exciting," the researchers said. "We have discovered that you can study the BRCA1 gene modifications in the laboratory and that they reflect with surprising precision what happens in a person with this variant, even if we work with cells in a dish, when we let's make some changes in the genomes of these cells, and look at where the right answers should be, they almost always align with what we see in patients. "

Previously, only a few different mutations could be examined at a time. Now, the way to edit a gene into a myriad of versions makes it easier to understand how our DNA works.

"We fundamentally classify all possible changes in the critical regions of the BRCA1 gene as behaving like mutations causing diseases or not," Findlay said. The researchers needed about six months to test nearly 4,000 mutations. They are expanding this work to cover the entire BRCA1 gene over the next two years.

Researchers are quickly publishing information on the newly available variants in the Brotman Baty database to help patients and clinicians try to understand what a test result might mean.

"Our hope," said Starita, "is that this database will continue to grow and become a focal point for guiding the interpretation of exploitable variants as they are observed for the first time in women. "

"The ability to study in a dish what will happen in a large-scale, living, breathing human being opens up many possibilities in medical genetics," Shendure added. Scientists plan to apply methods of modifying the saturation genome to other genes at risk for cancer.

"The study serves as a model," noted Findlay, "how to test for rare mutations in important genes that have great consequences for human health."