Dr. Jennifer Weiss
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Dr. Jennifer Weiss, University of Wisconsin-Madison, explains genetic variants of “unknown significance.”
Dr. Jennifer Weiss, University of Wisconsin-Madison, explains genetic variants of “unknown significance.”
In genetic testing, there’s three possible results: you can have a positive result, a negative result, and a variant of uncertain significance. A positive test result, which is counterintuitive to what everyone would usually think-- people think positive is good, but it actually means that we found a mutation that we were looking for. It means that we found a harmful mutation in the genes that we were testing. A negative test result, which is usually associated with bad, actually is a good thing for us. It means that, we searched all through your genes, and we found nothing. The results were negative --we did not find a mutation, or a harmful mutation, to explain your family history or your cancer risks. So I just want you to keep that in mind as I go on to kind of describe what genetic testing is and what variants of uncertain significance are.
And what is variance of uncertain significance?
So, genetic testing can be thought of as like a spell check for DNA, and the genes can be thought of as book chapters. So, when we’re reading our genes, when our body is reading our genes, they’re the instructions to tell our body how to make certain proteins. And the book chapters are the words that are telling our body what to do. Spelling mistakes can occur in these words and in these chapters. So, that’s what genetic testing is doing-- it’s looking for spelling mistakes within these book chapters. The spelling mistakes can be big, or typically harmful, which could be deletions, duplications of whole entire paragraphs within that chapter, that then cause a problem with the body’s understanding of the instructions. And the end result is just something that doesn’t work. You could also have very small changes, or very small mistakes within these book chapters. And some of these can actually be benign, or non-harmful, and just go into making us the unique individuals that we are. So, for example, in America, the way we spell the word “color”-- we spell it as “c-o-l-o-r.” In the United Kingdom, they spell the word “color” “c-o-l-o-u-r.” Neither of these is technically wrong, they’re just different. So that’s an example of a benign, or non-harmful, change-- you still know what that word means, you can still interpret that word within the context of that book chapter, and get the same end result. Another type of change, or spelling mistake, would be these variants of uncertain significance. And, this is where I think it’s a little bit confusing for people to understand, but just think of it as if it’s a word that you’ve never seen before, and so you don’t know if the spelling is correct or incorrect. We don’t know, if you read that word, if you’re still going to be reading it correctly, or if it’s a mistake that’s in a very small, unimportant part of the chapter. Or, if it’s a mistake that’s in a really big part of the chapter where the intended meaning of those instructions are completely changed, based on this small change. So, what happens with these variants of uncertain significance is that genetic testing companies over time will continue to gather more and more information about this change, or this spelling mistake in a gene. And their goal is to eventually reclassify this variant as either a variant of “known significance,” meaning that it’s potentially harmful, or a variant of “no known significance,” meaning it turns into a benign situation where this change actually doesn’t impact how the gene is interpreted, or the instructions are read. Over time, the vast majority of these variants get classified as benign, or non-harmful, but it does take time for all of this information to come together. So, as clinicians, when we have a patient with a variant of uncertain significance, we need to think of them within the context of their personal and family history, and not whether that variant is present or not present. So, for example, if I had a patient who came to clinic, and they had a father and a sibling with colorectal cancer below age 50, and no known hereditary cancer syndrome has been identified in the family-- we do the genetic testing, and I find a variant of uncertain significance. I would still tell that patient that they need to have earlier screening than the general population for colorectal cancer, and more frequent screening than the general population, regardless of whether that variant of uncertain significance was in that gene.
Dr. Jennifer Weiss, of the University of Wisconsin-Madison, explains polyposis syndromes.
Dr. Jennifer Weiss, of the University of Wisconsin-Madison, explains polyposis syndromes.
Polyposis syndromes are characterized by numerous polyps throughout the GI tract. In the colon, in the small intestine, and the stomach. These syndromes are rare and account for 1 to 2 % of all colorectal cancers. In the general populations, individuals may have sporadic polyps throughout their colon but generally have less than 20 to 30 in their lifetime. This means that each colonoscopy they might have a few polyps removed each time. In contrast individuals with polyposis syndromes will have anywhere from 30 to 40 to hundreds of polyps throughout their lifetime. The genes associated with increased risk of GI tract polyps are numerous and we are learning more and more each time data is collected and research is being done. These syndromes are inherited in a variety of ways, some are inherited autosomal dominant where an individual has one mutation from either their mother or father and then show signs and symptoms of the polyposis syndromes. Others are inherited autosomal recessive where they require a mutation from both their mother or father to show the signs and symptoms of the syndrome. And there is a third group which are called De novo mutations, meaning that that individual is the first person in the family to have that genetic mutation. So, there are no mutations in that gene in the prior generations of the family. However, the individual who is now identified to carry the mutation can potentially pass the mutation on to their children. Polyposis syndrome can be characterized based on the type of polyp that we see. Either adenomatous or hamartomatous polyps. These polyps are defined by a pathologist based on how the polyp looks under the microscope. Each syndrome has a different lifetime risk of different GI tract cancers and the colon, the stomach the small intestine. As well as different lifetime risks for cancers outside of the GI tract such as thyroid cancer or breast cancer. Our understanding of the lifetime risks of cancers associated with these genes is constantly expanding. So it’s important to keep in touch with your primary care provider as well as your gastroenterologist and your genetic counselor about any updates to the information we know about these genes and your cancer risks. How these polyposis syndromes present is very different. So, each syndrome has a more classic presentation. Either presenting in childhood or potentially mid to late adulthood. There is also a variety of presentations within a particular family. So we may have one family that has a mutation in one gene and the one person presents with hundreds of polyps throughout the GI tract. In the same family, an individual with the same mutation might only have 20 or 30 polyps throughout their GI tract in their lifetime. The polyps themselves also present with different symptoms. The hamartomatous polyps tend to present with bleeding causing low blood counts or anemia. They can also get so large that they can block the GI tract and cause abdominal pain and blockages in the intestine. And the adenomatous polyps while they don’t typically cause symptoms, they are pre-cancerous and can progress to cancer if they are not removed. How we remove these polyps depends on the size, the locations and how many polyps there are. We prefer to remove these polyps endoscopically with an upper endoscope or a colonoscope and avoid surgery if possible. However, when the polyps get too large or too many of them for us to remove with a scope, we do have to refer people to surgery. So individuals with polyposis syndrome are often referred to surgical removal of their entire colon with the potential of taking a small intestine, creating a pouch and attaching it to the anal canal or they might require segmental resections of different parts of the small intestine as well as the stomach. In this module you are going to hear stories from individuals with polyposis syndromes and hear about their experiences with increased risk of cancer. As well as the experiences they have on a day-to-day basis from the prophylactic surgeries that they have had to remove their colons or parts of their small intestine and stomach. As I mentioned before, polyposis syndromes are rare but our information that we are learning about the genes that are involved as well as the lifetime cancer risks is constantly expanding. So, it is very important to keep in touch with your providers. Our knowledge of the cancer risks the genes that are associated with these syndromes as well as how to manage and survey people over their lifetime is a dynamic process, and gets updated on a regular basis.