Genetics, Genetic Testing, and Breast Cancer: Part 1

Jamie DePolo: Hello, everyone. Welcome to this edition to the Breastcancer.org podcast. I’m Jamie DePolo. I’m the senior editor, and today we are going to be talking with Cristina Nixon, who is a licensed certified genetic counselor. And this is the first in a series of three podcasts talking about genetics, genetic counseling, and genetic testing. And we know this is a big issue for a lot of people; people are very interested in it. So we’re very delighted that Cristina has joined us for these three podcasts.

Cristina is a licensed certified genetic counselor, as I said. She’s with the Cancer Risk Assessment and Genetics Program at Main Line Health in Pennsylvania. In addition to counseling patients, she also assists with research, including, most recently, a study looking at multigene panels in BRCA1- and BRCA2-positive families. Cristina also has completed the City of Hope’s intensive course in cancer risk assessment. And today we’re going to be talking about genetics and breast cancer. Cristina, welcome to the podcast.

Cristina Nixon: Thank you.

Jamie DePolo: So, to start with, let’s start very basic. What are genes? Because we hear all this stuff about genetic testing, genes and cancers, genes and people. So what are they?

Cristina Nixon: So, genes are basically just short segments of DNA that provide instructions telling our cells how to perform different functions. DNA is made up of four different chemicals, which we can abbreviate with the letters A, C, T, and G, and each gene has its own unique spelling of this chemical code which can actually be hundreds to thousands of letters long.

The cell is then able to interpret the unique sequence of these letters as instructions telling it how to perform different functions. And these functions could vary from things like physical traits, things like hair color, height, eye color, as well as bodily functions like digestion, and even at the cellular level, it could tell a cell how often to grow and divide. Genes are also in every cell of our body, and they’re always inherited from both of our parents.

Jamie DePolo: Okay. And so what makes a gene abnormal when we talk about an abnormal BRCA1 gene, and are there different types of abnormalities?

Cristina Nixon: Sure. An abnormal gene results when there is an alteration that occurs within that chemical code or within the DNA of a gene. And basically, because of this alteration in the chemical code, it prevents the gene from not being able to interpret those instructions, and so it’s not able to function as well, or sometimes it’s not able to function at all. So you could think of it like a spelling mistake in your DNA that disrupts, again, those instructions. Some types of alterations within genes are not harmful, those are what we call benign changes, and then there are alterations which definitely are harmful, and we refer to those as mutations.

Jamie DePolo: Okay. So I could have an abnormal gene, and I’d never know it because it’s not causing any problems?

Cristina Nixon: Correct. Yes.

Jamie DePolo: Okay, and that would just be abnormal, but if I had a mutation, then that’s a problem?

Cristina Nixon: Right. And sometimes even with disease-causing mutations, you may not know that you have that mutation either just because it hasn’t shown up yet, or, in some cases, you may never develop the disease. Sometimes it’s just a predisposition where you’re at higher risk of developing disease, but you necessarily don’t go on to develop it.

Jamie DePolo: Okay. Now, do most people have some abnormal or altered genes? I mean, is that common?

Cristina Nixon: Yes. Everyone has abnormal genes. In fact, most mutations are actually acquired throughout life either from exposure to something in the environment, or due to lifestyle factors like smoking, or just simply because of mistakes that happen in the DNA as cells are growing and dividing. There are also mutations that are inherited from one or both of our parents.

Jamie DePolo: Okay. And I’m going to ask you this, and I know it’s a big, long term, but so there is a difference between an inherited mutation and an acquired mutation?

Cristina Nixon: Yes. Yes. So, inherited mutations are actually in every cell of the body because they’re passed down from one parent or both parents, whereas an acquired mutation usually only occurs in one cell, in one gene of one cell within the body.

Jamie DePolo: Okay. Is one or the other more harmful to a person, or are they equal, or does it matter?

Cristina Nixon: So, for example, take cancer. Most cancer is caused by acquired mutations, versus a small percentage of cancers are because of an inherited mutation, but it’s actually in combination with an acquired mutation as well. So when it’s hereditary, it’s a combination of inherited mutation plus acquired mutation. So that’s kind of a tough question to answer as far as what is worse. With inherited mutations when we’re talking about cancer, usually the cancers, when they happen, will happen at younger ages, and sometimes a person could develop more than one type of cancer or multiple cancers throughout their life because of the inherited mutation.

Jamie DePolo: Okay. Now, for the BRCA1 and the BRCA2 genes, I’m going to ask you what they do, but we talk about them as being inherited mutations. Are they ever an acquired mutation, or is that always an inherited problem?

Cristina Nixon: So, there can also be acquired mutations in BRCA1 and BRCA2. So when we think about our genes... Let’s take BRCA1, for example. We actually have two copies of every gene, because one copy comes from mom. The other copy comes from dad. So, with BRCA1, if a person has inherited a mutation in the BRCA1 gene, it means that, in all of their cells, they have one copy of the gene that they inherited with the mutation, and they have one working copy in all of their cells. So in order for a cancer to develop, at some point throughout their life, something has to happen in a single cell to that working copy of the BRCA1 gene. And if a mutation occurs in that working copy, then that is when that cell is at risk to grow into a tumor, because it’s then lost both sets, or both copies, of the BRCA1 gene. And normally what BRCA1 does is it’s a tumor suppressor gene, as well as BRCA2. Their job is to actually prevent cells from growing into tumors. So then there’s a mutation. That’s what’s increasing the risk for certain types of cancer, because of losing that set of instructions.

Jamie DePolo: Okay, and I’m assuming that’s why everybody who has a mutation in one of those genes isn’t diagnosed with cancer, because they may still have that one working copy that’s working just fine?

Cristina Nixon: Correct.

Jamie DePolo: Okay. Okay. So we know that having an abnormal BRCA1 or BRCA2 gene is linked to a higher risk of breast cancer in both men and women, as well as other types of cancer. What are these other types of cancers that are more common in people with these mutations?

Cristina Nixon: Sure. So, the second highest cancer risk in women who have a BRCA1 or 2 mutation is ovarian cancer. The ovarian cancer risk is up to 44% over a lifetime in women. Other cancer risks that you might see do include pancreatic cancer as well as melanoma in both men and women that have a BRCA mutation. Those risks are each about 7%. And then in men, men who have a mutation, they also can have breast cancer risk not nearly as high as what it is in women. It’s up to 6% over a lifetime, and also they have a prostate cancer risk of about 20%.

Jamie DePolo: Okay. Okay. So if there’s a history of another cancer in a woman’s family, say pancreatic cancer, for example, in addition to breast cancer, are there other abnormities that you talk about with somebody that you’re counseling? I guess I’m wondering if there are kind of suites of genes that go along with specific cancers.

Cristina Nixon: Yes. Absolutely. So when we take a family history as a genetic counselor and even with your physicians or nurses, whoever is asking about cancer family history, it’s important to tell them about all of the cancer in the family, not just breast cancer. Even if breast cancer is your main concern, we still want to know about all of the cancer in the family because it really helps to guide what genes we focus on when we’re talking with you about genetic testing. Genetic testing for hereditary breast cancer has expanded so much beyond just BRCA1 and BRCA2.

There are panels of genes now that we can test for linked with hereditary breast cancer, but then each gene that we test for is also associated with its own sort of spectrum of cancer. So, for example, you asked about pancreatic cancer in addition to breast cancer. One additional gene that we would definitely think of in that case would be a gene called PALB2. It has similar risks to the BRCA2 gene when there’s a mutation in that gene as far as the breast cancer risk. The pancreatic risk isn’t as well defined in the PALB2, but we know that there is a risk for it.

Jamie DePolo: Okay, and I guess when you’re counseling somebody, too, do you talk about more than cancers with people? I’m wondering, autoimmune disorders or anything like that, does that play into this genetic thing, or is it really just looking at cancers and known diseases?

Cristina Nixon: It’s really looking at just cancer as well as benign tumors. We don’t go so much into autoimmune disease, or cardiovascular disease, or other inherited conditions. We try to keep it just to cancer-related genes.

Jamie DePolo: Okay. And I wanted to ask, too, you mentioned that PALB2 gene. What are some of the other genes that are linked to a higher risk of breast cancer?

Cristina Nixon: Sure. There’s actually a number of them, and I guess I’ll focus on the genes that are classified as high-risk breast cancer genes.

One of those genes is called TP53. This is a gene that has a very high risk of premenopausal breast cancer. Women are young, they’re usually in their 20s or 30s if they have a mutation in this gene and happen to develop breast cancer, and it’s associated with a syndrome called Li-Fraumeni syndrome. There’s a very high risk of developing multiple types of cancer when there’s a mutation in that gene.

There’s another gene called PTEN, where the breast cancer risk is anywhere between 50 and 85% over a lifetime, and other cancers that we might see include uterine cancer and thyroid cancer when there’s a mutation in that particular gene. And it’s associated with a syndrome called Cowden syndrome. Another gene that I can think of is CDH1. This is a gene where there’s a very high risk of a specific type of stomach cancer called diffuse gastric cancer, as well as up to a 52% risk of breast cancer, in particular the lobular type of breast cancer.

And then the last high-risk gene is a gene called STK11, which is associated with a syndrome called Peutz-Jeghers syndrome. And women have up to a 50% chance of developing breast cancer when there’s a mutation in that gene, along with a spectrum of other cancers as well.

Jamie DePolo: Okay. Yeah, that is quite a few, and I’m just curious, we hear so much about the BRCA1 and BRCA2 -- is it because these other genes, the connection was more recently found?

Cristina Nixon: I wouldn't say that it’s necessarily more recently found. It’s just that these genes are each a lot less common. We see them a lot less often than we see BRCA1 and 2. BRCA1 and 2 are still the most common genes that we see with hereditary breast cancer. So that’s why we don't hear about them as much.

We’re hearing more about what we call moderate-risk genes, which include that PALB2 gene that I mentioned earlier. While in some families, the breast cancer risk does seem to be similar to families that have a BRCA2 mutation as far as breast cancer risk, there are other families where that risk seems to be lower when there’s not as much family history, maybe closer to a 30% lifetime risk.

And there are two other genes, CHEK2 and ATM, where these breast cancer risks are more in the 25–30% range rather than those high risks. High risk is defined as between 50 and 80% or higher over a lifetime.

Jamie DePolo: Okay. Okay. Oh, that’s interesting. I didn't know that they were that uncommon, those other genes. Okay. That’s good to know. And all those can be tested for and acted upon? Is that right, or no?

Cristina Nixon: That’s right. So all of the genes I just talked about, including the moderate-risk genes, there are actually national guidelines that physicians can use to determine what type of screening women may need, or even preventive surgery for the high-risk genes can be considered. So yes, there’s definitely action that can be taken if the mutation is found in any of them.

There are a subset of genes where they’re very new to genetic testing and they’re linked with breast cancer, but we may not be able to say at this point in time how high that breast cancer risk actually is. And so it’s harder in those cases with those genes to necessarily know what to recommend at this point. So, in some of these panels of genes that we’re testing for, there is a section in some panels that includes these genes where we don’t know as much about, and we do have that conversation ahead of time with patients to make them aware that, if they go ahead with this test, we may find a mutation in the gene that we don't know as much about at this point in time, but the hope is that, over time in the future, we will have more information about those genes as well.

Jamie DePolo: Okay. When somebody has a panel test, the genes that are tested for in that, is it always the same, or can you kind of pick and choose depending on someone’s history?

Cristina Nixon: So, that’s a great question. It really depends on the lab that we’re using. There are multiple labs now that are doing these gene panels, and some of the labs do allow us to customize the panel to pick only the genes that are appropriate, again, based on the family history as well as pick genes that a person is truly interested in learning about. You know, there may be a gene that a person really just does not want to know if they have a mutation in for various reasons. So we’re able to exclude that from the panel.

But then there are other labs where the panel is pre-defined. You can’t customize it. It’s an all-or-nothing event. We can’t pick and choose the genes. So, in some cases, that can be a good thing because it may actually include genes that we wouldn't necessarily think to test for, but we may incidentally pick up a gene mutation that we weren’t expecting to find. Now, I say that can be a good thing because we may learn about cancer risk that we wouldn't have otherwise known about and can make better recommendations to a person based on that finding.

But in some cases, a person may not necessarily want that unexpected test result, again, if there’s a very high risk of developing a stomach cancer, for example, where the recommendation might be to actually remove the stomach preventively. That is a gene that we do specifically point out in a lot of cases because, again, that could be extremely difficult to learn about, and a person may be upset that they even had a test that included that gene if they didn't know about it ahead of time.

Jamie DePolo: Sure. Sure, and that goes into a lot of the counseling, which is what we’re going to talk about in podcast two.

And one more question before I let you go on this one. Do we know what percentage of women and men in the United States have an inherited mutation that’s linked to higher breast cancer risk? Has anybody been able to figure that out?

Cristina Nixon: So, it’s a pretty low risk in the general population. Again, BRCA1 and BRCA2 are the most common genes associated with hereditary breast cancer, and in the general population, the chances of carrying a mutation in either of those genes is anywhere between 1 in 500 to 1 in 800. So it’s pretty low. Now, there are certain ethnicities where that rate is higher, specifically in individuals who are of Eastern European Jewish decent, also known as Ashkenazi Jewish individuals. They have a carrier rate of 1 in 40. So 1 in 40 individuals will carry a mutation in BRCA1 or BRCA2. So we do also take into account ancestry when we’re taking a family history as well.

Jamie DePolo: Okay. Yeah, that makes sense. Are there any other groups, or is that predominantly the Ashkenazi Jew?

Cristina Nixon: It’s predominantly Ashkenazi Jewish individuals. There are some other populations where there are higher frequencies, including Icelandic populations and Dutch as well.

Jamie DePolo: Okay. Good to know. Well, Cristina, thank you so much. This has been so incredibly enlightening, and I’m really excited for parts two and three of this, and thank you!