BRCA1 and BRCA2 gene mutations - Genetics

****Caveat: I am just a physiatrist,(PMR doctor) not a genetics specialist. But... suddenly very interested in genetics. ****

This is an edited copy of some explanations about BRCA gene mutations from the FORCE site.

BRCA1 is actually a breast and ovarian cancer preventative gene, on the 17th chromosome, which when certain mutations - abnormalities that interfere with proper gene function - occur, then the person carrying it is at high risk of developing one or both cancers.

Each person carries 2 - 17th chromosomes one from their mother's egg and one from their fathers sperm. As a person's body produces each egg and each sperm half receives one or the other chromosome. Usually a person would have one normal and one mutated gene. ( I guess most people not surfing this web site have 2 normal copies. ) So, the 50/50 chance that the offspring will get the defective gene or the normal gene, at the time of conception. The HBOC (hereditary breast and ovarian cancer syndrome) is an autosomal dominant inheritance situation, so having one defective (not sure that sounds any better than mutant) gene is necessary to cause all of the cancer risk associated with the syndrome.

(Autosomal means on a non sex linked chromosome, so you can get it from mom or dad. Dominant means that you only need on copy of the gene to have the effect)

As a carrier of a BRCA1 mutation, your daughter or son has a 50% theoretical chance of getting or not getting the gene, decided at conception, assuming her dad does not also carry a gene mutation(and that you have one normal BRCA1 gene). Nieces are only at risk if their related parent is positive for the BRCA1 gene mutation, 50 % chance, so testing of the related parent is the first step in determining their risk.

As far as manifestation of the gene mutation, this term is called penetrance, and the studies show that there is a very high penetrance, meaning high likelihood that the presence of the mutation will raise risk for causing a cancer. (this is more complicated that in normal genetics, as the mutation only interferes with body’s ability to heal cellular mutations that can cause cancer, so some carriers will never get cancer.

So the only loophole is that statistically only half the offspring should get it. Unfortunately for many of the families listed here, the stats don't always hold. In my family, for instance, I have 2 sisters, with Dad being positive for a BRCA1 mutation. So... I have a 50% chance of testing positive, and each of my sisters have a 50% chance. And that means only a 12.5% chance that all three of us are negative, and a 12.5% chance that all three of us are negative. There are a bunch of different mutations, and appear to act a little differently, so I am not confident that my avoidance of BC or OVCA until age 43, is any indicator of what my results might be.

Everything about applies equally to the BRCA2 mutations, except that it is carried on the 13th chromosome. BRCA2 mutations cause breast cancer in men, and the cancer rates for women are somewhat different.

Response to question about penetrance and risk:
You raise a very good question, and point out interesting issues about BRCA and hereditary breast and ovca(ovarian cancer) statistics. It would be wonderful if your hypothesis(that the same mutation carries lower risk in families without high incidence of cancer) was true, but it is not, as far as my reading indicates. Below is a long winded explanation.

****Keep in mind that this is a very complex syndrome with a lot of variables, so not everything applies to every person finding this message board.****

*****I will be going to a genetics counselor whether or not my test is positive, to have someone professional re-assess my specific situation.*****

What we know about genetics comes initially from observing non - pathologic traits, over several generations, by observation. Mendel studied peas, human geneticists studied eye color, hair color, whether you can roll your tongue, whether you can taste sour things, blood type etc. In these areas, penetrance is very high, and it is easy to see how the genes behave because you can look at them and see that if mom has blue eyes and dad has brown eyes, that if all of the kids have brown eyes, that brown eye genes are dominant over blue eye genes, then in the next generation if the brown eyed kids marry brown eyed kids with the same heritage, that 1/4 will have blue eyes, because all the kids from the first generation got one blue from mom and one brown from dad. (this example assumes that dad is brown/brown - 2 copies the same)

Moving in to medical genetics, there are well studied genes autosomal genes in some diseases where the severity of the symptoms vary. (certain types of muscular dystrophy) This is a low penetrance type genetic flaw, meaning that someone can have the gene mutation, but not get the disease, or a very mild case of the disease. (I like flaw) Other genetic disorders are autosomal dominant like Huntington's disease which has a high penetrance, meaning if your Dad shows symptoms of Huntington's in his 40s and 50s, you have to decide to get tested and if your test is positive you know that you will face the same fate. This is a high penetrance gene, meaning that everyone with the gene gets the disease equally as severe.
(Autosomal means on a non sex linked chromosome, so you can get it from mom or dad.)

The studies on breast cancer heredity and ovarian cancer heredity started by looking at families where many members of many generations had breast or ovarian CA. The statistical studies showed that it acted like a high penetrance autosomal dominant gene. The DNA studies in these families allowed scientists to start finding the BRCA1 and BRCA2 gene mutations. It is a bit harder to make inferences about exactly how the heredity works with regard to penetrance because the mutations don't cause cancer, just impair one's ability to fight the cell level mutations that happen all the time. So there is a baseline rate of breast CA that everyone is at risk for and the heightened rate that gene mutation carriers have. The crux of the penetrance issue is whether everyone with a gene mutation is at the same high risk as everyone else or not.

That gets to penetrance.

This is where I stopped learning about this stuff in school and from my research about my mom. As the gene was identified, the hope was that there was a variable penetrance to the gene mutations, meaning that the folks with the families where lots of people got cancer had the same mutation of unsuspecting people out in the world, but that their mutation caused worse problems for some reason. I was really hanging my hat on this possibility.

So, the scientists went back to the same type of families and studied whether they had mutations, and when they studied other people who had the mutations, but did not have the same family history. Unfortunately, they found that the people in the previously known high risk families where there were known mutations were the ones getting cancer, and the ones who did not, did not have the genes. (50% loophole) They also found that the people without previously known high risk families who had the gene mutations got cancer just like the high risk families(slightly lower percentages 75% BC risk vs. 85% BC risk for the high risk families).

Hence high penetrance and that loophole does not actually exist. The other thing that makes this all so complicated is that not all of the high risk families have BRCA1 or BRCA2 mutations that we know about, so we can assume that there are other genes somewhere that control hereditary breast and ovarian cancer syndromes, in addition to the fact that they are finding different mutations all the time, and that new mutations can crop up spontaneously. This is why a positive gene test is usually considered to make someone high risk, but a negative test is only useful in a known high risk family if the affected members of the previous generations test positive and you test negative. Sorry for the very long winded answer. Very complicated stuff.

Challenge from another site member, stolen verbatim 2/25/2007, 8:15 pm Great explanations, But I would also add, that as it says on this website, there is still debate about the penetrance rates for any individual because there are so many different mutations (literally hundreds) and it is likely that they do not all behave exactly alike. That is why you will find different risk rates quoted - different studies have shown different results. There are also probably other factors and maybe other genes that influence the penetrance in certain families. We really don't know enough yet to give any individual risk rates with great accuracy. Even in what appear to be the highest risk families there are individuals who are known to carry the gene and have never had cancer.

I argued long and hard about some of this with my geneticist (she is a colleague and friend - so that helps) who was trying to convince me that my risk was in fact lower than what I imagined - she was quoting standard BRCA2 risks from the most recent community based studies which are significantly lower than the original risks that were devised from studies on only very high risk (high penetrance) families. I was using my family as a guide (virtually no woman has survived it yet in my family). I agreed with her explanations but could not accept them for me. In the end I decided that really no geneticist was able to accurately tell me my risk at this point in time and whatever my risk is, it is high enough that my decisions would be the same whether my penetrance was 45% or 85%. Understanding these risks is not an easy or straightforward matter. Worth going over again with geneticists or genetic counselors - several times if you need to!

My response 2/25/2007, 10:48 pm
I agree completely. Despite strong motivation, I could not find enough specific to the mutation my family carries to make me feel confident of exactly where my risk lies. Reading the site, I can hear several types of stories, from women with the same classes of mutations. There is much more research to do. Hopefully, as all of the women on the Force web site(and others getting tested and taking action) are taking our futures into our hands, we will change the shape of this syndrome. (unfortunately making it even harder to study.)