How did this mutation get into my family?
Most changes (also called mutations) in genes that cause an increased risk for cancer are inherited from a parent. But sometimes a gene mutation can arise as a new (also called de novo) mutation that occurred while that person was developing as a fetus, or even in mom’s egg or dad’s sperm, that are usually random. There are two main types of gene mutations: germline mutations and somatic mutation.
Germline gene mutations are changes in genes that are in every cell of someone’s body. They were born with it, and as their cells kept dividing to keep their body going, every cell that got made had that same change in the same gene. Somatic gene changes are mutations that happen usually to one or a small group of cells that only affects a small part of the body.
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To the point: This is a good question and one that is asked frequently. The short answer is no, but keep on reading to learn more about why this is the case.
Germline genetic mutations do not “skip” generations. If an individual has the mutation they are at an increased lifetime risk of cancer, and they have a 50% chance to pass the mutation on to their children (see Autosomal dominant inheritance). Sometimes mutations look like they skip a generation because in one generation there may not be a person that develops a cancer. This is because most of the mutations do not result in a 100% lifetime risk of cancer. Although an individual that has one of these gene changes may never develop cancer themselves, they still have 50% chance of passing the non-working gene on to their children.
This is another common misconception. Let’s use the BRCA1 gene as an example to illustrate why it is important to look at BOTH sides of the family history. Let’s say we have a patient who doesn’t have a concerning history of cancer on her mother’s side of the family, but her father had three sisters and his mother that all had either breast or ovarian cancer. One of the patient’s aunts with ovarian cancer tested positive for a BRCA1 mutation. If she has both of the same parents as the patients father, there is a 50% chance that the patient’s father also inherited the BRCA1 gene change that increases the risk for cancer.
This is where it gets a little more tricky. The biggest increase in cancer risk with BRCA1 is for breast and ovarian cancer. Men generally don’t have an amount of breast tissue that would significantly increase the risk for breast cancer, and men don’t have ovaries. BRCA1 changes also increase the risk for prostate and pancreatic cancers, but the lifetime risk for pancreatic is relatively small, and prostate cancer is not uncommon as men get older. So, if a man inherits a BRCA1 change, he’s not at a significantly elevated risk for the two cancers we most associate with this gene. That means his risk to develop one of those cancers is markedly reduced. But, if he carries the change in BRCA1, there is still a 50% chance that he would pass it down to any of his children. If he were to pass this down to a daughter, she would have a significantly higher risk for breast and ovarian cancer. Because men are not at as high of a risk as women to develop cancer with a BRCA1 mutation, it can look like it skips a generation if it passes through one or several males in a family. When a female inherits it from her father and develops cancer, and the closest known relative that also has cancer is two or more generations before her, that also gives the appearance that the cancer risk is skipping one or multiple generations.
Also a good question. With BRCA1 and BRCA2 gene changes, the highest increase in risk is for breast and ovarian cancer. The highest risk for male breast cancer with mutations in either of these genes is 10%. The average woman’s lifetime risk for breast cancer is 12%. Adding to that, men do not have ovaries, so they do not have a risk for ovarian cancer.
Changes in BRCA1 and BRCA2 also increase the risk for pancreatic and prostate cancer. While there are no established screening guidelines for pancreatic cancer, if a male is known to carry a BRCA mutation, earlier screening for prostate cancer may be recommended. Changes in BRCA2 also increase the risk for melanoma, so that may be helpful for both the patient and their physician to know.
Another potential reason for a male to do testing is to provide more information for other family members, including his children. If a male is found to carry a BRCA mutation, there is a 50% chance he will pass it down to any children he has. If he passes it down to his daughter, she could have up to an ~80% lifetime risk for breast cancer, and up to a ~40% lifetime risk for ovarian cancer.
There are times in a family where a male has had a related cancer (prostate, pancreatic, or melanoma for BRCA), and is the only member of the family alive that has had a BRCA-related cancer. Generally in a family, we want to start genetic testing for hereditary cancer risk with someone who has had a related cancer. If there is a mutation in one of these genes that increases the risk for cancer, a member of the family that has had a related cancer is the most likely person to carry it. So if a male is the only living member of a family that has had a related form of cancer, their test results would be most helpful in offering testing to other family members, as well as putting their test results into appropriate context.
We talk a lot about the BRCA genes, but there are dozens of other genes that have a link to hereditary cancer. Each gene can be associated with various different types of cancer, so make sure to discuss any questions or concerns with a genetic counselor.
To the point: When you meet with your genetic counselor or other health care provider to discuss genetic testing, they will typically suggest beginning genetic testing in the family on an individual who has been diagnosed with cancer. Strongly take this into consideration if it is at all possible in your family as it will typically lead to the most accurate testing possible and thus the most accurate estimation of the cancer risks for you and your family members.
Ideally genetic testing would always begin with a person in the family that has been diagnosed with cancer. Of course, this is not always possible if all family members with cancer in the family have passed away or otherwise unwilling or unable to undergo genetic testing. In these situations, genetic testing in family members who have not been diagnosed with cancer may still be of value and provide good information. However, starting testing with a family member who has or has had cancer is the way to get the most accurate genetic testing results for other family members.
If we test a family member who has cancer and find a change in a gene that we can say is responsible for causing the cancer, we now know what to test other people in the family for. For example, if you have an aunt who has ovarian cancer and was found to carry a mutation in the BRCA2 gene, now that we know what is causing the increased risk for cancer in your family, we can offer testing to others. If they are also found to carry this gene change, we know they share the increased risk for cancer and we can offer them options for early detection or prevention. If they are found not to carry this gene change, then we can say they should have the same lifetime risk for cancer as the general population (unless they have a strong history of cancer on the other side of their family). This is called an informative negative, or a true negative.
If the person who has or has had cancer undergoes genetic testing that is negative, we would not recommend genetic testing for family members who have not had cancer. If there was a gene mutation running in the family, the most likely person that we would expect to find it in is someone who has already had cancer. If that person tests negative, we wouldn’t expect that anyone in the family who hasn’t had cancer would have a positive test result.
A negative test result in a family member without cancer is called an uninformative result. Let’s say your aunt with ovarian cancer was unable or unwilling to undergo genetic testing. Having a family history of ovarian cancer meets criteria for genetic testing, so we could move ahead with testing for you. If your tests are all negative, we know your risk for cancer is likely reduced, but we can’t say that it is as low as the general population. Because your aunt was never tested, we cannot say for sure what caused her ovarian cancer. It is possible that her cancer could have a genetic cause, but that you just didn’t inherit it. Or it’s possible there is a change in one of the genes that you were tested for that increases the risk for cancer that we don’t know how to test for yet. There could also be other genes that we don’t know about yet that increase the risk for ovarian cancer that could be running in your family.
Sometimes the best person to test in the family is not the patient OR someone who has had cancer. For example, if your paternal grandmother (your father’s mother) died of ovarian cancer and there are no other family members on that side who have had cancer, your dad would be the best person to test. If we can’t start testing with someone in the family who has had cancer, then our next best step is to start with the person who is most closely related to that person. Because your dad is more closely related to your grandmother, it would be best to start testing with him.
Figuring out who the best person to start genetic testing with in the family may be difficult to figure out and not straightforward. Genetic counselors are specialists who can assess your family history to determine if there is an increased risk for hereditary cancer in your family, and who the best person would be to start testing with.