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Men with breast cancer
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Special populations: People who have a Variant of Uncertain Significance in a gene associated with cancer risk.
Ever since BRCA1 was discovered, researchers have been trying to understand which of the thousands of possible DNA changes in this gene increase cancer risk and which are harmless changes. A new study in Nature reports how a cutting-edge technology called “genome editing” may be used to classify changes—known as variants of uncertain significance-in BRCA1 as harmful or harmless. Once validated, this same technology may be used to classify variants in other genes. (9/29/18)
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How a new technology could be used to help classify BRCA1 Variants of Uncertain Significance.
Genetic testing is not always straightforward. While most people who have genetic testing will test positive or negative for a gene mutation that increases cancer risk, some test results are inconclusive. Studying whether a “variant of uncertain significance (VUS)” is harmful or harmless is important, because currently their effect on cancer risk is unknown.
In the past, fewer people had genetic testing for BRCA and other genes associated with increased cancer risk and testing was most available to people with a personal and family history of cancer. As the cost and availability of genetic testing have gone down, more people have had testing, including people who do not have a personal or family history that suggests a mutation.
Experts often use the family cancer history to help people with a VUS understand their risk, but family history alone is not an accurate tool for assessing breast and ovarian cancer risk, especially in small families or those families with mostly men. Finding better tools to figure out which changes are harmless and which are harmful will help genetics experts advise people with VUS results of their cancer risk.
This new method could be a game changer for evaluating VUS in BRCA1 and other genes, but this technology will need to be further validated using clinical data.
CRISPR-Cas9 is a simple, yet powerful technology that allows researchers to easily “gene edit” or modify the DNA sequence of a gene. Researchers can then then see how that change affects the gene’s function. (Scientists have other gene-editing technologies, but the newer CRISPR technology is faster, easier and more effective.)
In this study, researchers used CRISP-Cas9 technology to change DNA instructions in BRCA1 in laboratory cells. They then observed how these edited genes functioned. Almost 4,000 possible BRCA1 changes were analyzed.
The results, although not perfect, were strikingly accurate.
It’s important to understand that this technology does not impact most BRCA1 genetic test results. This technology applies mostly to people who received results of a VUS.
The ability to accurately classify nearly 4,000 BRCA1 changes may prove to be a much-needed tool that researchers can use to reclassify VUS from unknown to known (harmful or harmless).
If you have had genetic testing and received a report that you have a VUS, this technology—once it has been validated—may provide you with more information about your risk.
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BRCA1 changes are classified in three ways: as benign variants that cause no concern; as deleterious variants that can confer a high risk of cancer; and as variants of uncertain significance or VUS, which have an undetermined effect on cancer risk.
As of January 2018, most single base-pair changes in the BRCA1 gene are classified as a VUS. These changes are rarely seen in more than a few people. Determining whether or not these rare changes affect cancer risk is a significant challenge. This difficulty is also reflected in the fact that hundreds of changes in BRCA1 have conflicting classifications between different labs.
The study authors used an innovative approach called “saturation genome editing.” Using this technology, the authors were able to make almost 4000 single-base pair changes in BRCA1. These changes were made in regions that have been shown to be important to BRCA1 function. When a change caused a cell to die, it was classified as harmful; in cells that lived, the change was classified as harmless.
Can we develop a robust, large-scale way to classify DNA changes in BRCA1?
This research was conducted in a single human cell line (a cell line is a group of cells in a petri dish that have all descended from a single cell). However, results were compared to a BRCA1 database that uses clinical data to classify changes in BRCA1.
Saturation genomic editing was applied to key regions of BRCA1. Both exons (regions that code for the BRCA1 protein) and introns (regions that do not code for the BRCA1 protein) were tested. Researchers classified nearly 4,000 changes as harmless or harmful.
Researchers compared their results from another published studys and to an internationally recognized data base that uses clinical information to classify changes in BRCA1. The results, although not perfect, were strikingly accurate:
Although not perfect, the results of this study are very accurate.
This study used a novel approach to classify nearly 4,000 changes in BRCA1. However, the changes studied were only in a portion of the BRCA1 gene (changes studied were in 13 exons and surrounding introns out of the 24 exons and introns in BRCA1). This study is limited in that currently, what provides confidence to variant classification is the availability of sufficient clinical data to assign risk to a given variant. More clinical data will be needed to validate this approach.
If validated, this approach could be a major advance over previous attempts to study the consequence of a change in BRCA1 in a research setting. However, serious consideration should be given to how best to integrate this assay into reclassification of current VUS and new never-before-seen changes in BRCA1 that are sure to appear.
This research could be a very important addition to cancer genetics generally. This approach may possibly be used to better classify changes not only in untested regions of BRCA1 but in other cancer predisposing genes.
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FORCE Information: Genetic Testing: Types of test results
XRAYS Category: Genetic Testing
Thoughts From FORCE Blog: Headline Hype: Media Report on BRCA1 Variant Research Plays on Fears
1. Findlay GM, Daza RM, Martin B, Zhang MD, Leith AP, Gasperini M, Janizek JD, Huang X, Starita LM, Shendure J. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0461-z.
2. Starita LM, Islam MM, Banerjee T, Adamovich AI, Gullingsrud J, Fields S, Shendure J, Parvin JD. A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 Missense Substitution Variants on Protein Function. Am J Hum Genet. 2018 Aug 24. doi: 10.1016/j.ajhg.2018.07.016.
3. Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Martin CL, Nussbaum RL, Plon SE, Ramos EM et al. ClinGen — The Clinical Genome Resource. 2015. N Engl J Med. 372:2235-2242. DOI: 10.1056/NEJMsr1406261