Is cancer inherited?

October 11, 2007

Related Topics:
Complex traits,

A curious adult from Michigan asks:

"Is cancer inherited?"

That's a great question, and the answer is a lot trickier than you might guess! Most cancers are not inherited -- they just happen.

Sometimes you can inherit an increased risk of cancer. And very rarely certain types of cancer can be passed down through generations.

Clear as mud, huh? To understand all of this, let's take a crash course in cancer biology.

As we all know, our DNA is a blueprint that makes us who we are. Inside our cells, DNA is organized into long strings called chromosomes. Along these chromosomes are segments of DNA called genes.

Genes are the instructions for making the proteins that do all the work in our cells. Some of our genes have instructions for making proteins that tell our cells to grow and divide. And some have the instructions for telling our cells to stop growing.

Genes that tell cells to grow and divide are called oncogenes. These genes are like the accelerator pedal in a car. Genes that tell cells to die or to stop dividing are called tumor suppressor genes. These genes are like the brake pedal.

Classic car
Some genes are like an accelerator (oncogenes) or a brake pedal (tumor suppressor genes). (Image: Wikimedia Commons)

Normally, our cells have a perfect balance of oncogenes and tumor suppressor genes. Our cells divide when they need to divide and stop dividing when they're supposed to stop. It's just like a car that can accelerate when the stoplight turns green and stop when the stoplight turns red.

But in cancer, something goes wrong. The cells just keep growing or they refuse to die. The accelerator gets stuck or the brakes stop working and the car runs the red light. What goes wrong in the cell?

As you might suspect, something goes wrong with an oncogene or a tumor suppressor gene. Technically speaking, one of these genes gets a mutation.

Mutations are simply changes in our DNA. They're pretty common and usually don't have any effect. Unless they happen somewhere important.

Imagine that one of these mutations turns on an oncogene. Now the accelerator is stuck and the cell keeps growing. Or the mutation turns off a tumor suppressor. Now the brakes are broken and the cell refuses to die. These are two of the most common ways for cancers to happen.

DNA mutation
DNA mutations can cause cancer (Image: Berkeley)

But in most cases, cancers like these are not passed on to our children. Why not? Because we get our DNA from sperm and egg cells.

Imagine a woman has lung cancer. She was born healthy, but cigarette smoking damaged the DNA of one of her lung cells. This cell started to grow uncontrollably. But the DNA in the woman's eggs is still perfectly normal. So she won't pass on her lung cancer to her kids.

This is why cancer is so rarely inherited. Since cancer often happens because of a DNA accident in a cell other than an egg or a sperm, it is not passed down.

But there are some cancers that can be passed down. In these cases, mom or dad has a pre-made DNA change that turns on an oncogene or shuts off a tumor suppressor gene. There is no need for a mutation to cause the change.

For example, broken versions of a gene called RB cause an inherited childhood eye cancer called retinoblastoma. Shortened versions of the APC gene cause inherited colon cancer. And differences in the DAPK1 gene -- which helps tell cells when they should die -- are involved in many inherited cases of chronic lymphocytic leukemia (CLL).

Some DNA changes cause an increased risk of cancer

These cases are all very rare. More commonly, someone can inherit an increased risk of certain cancers. This is what happens in most cases where a cancer runs in the family.

Let's say breast cancer runs in my family. This doesn't mean that everyone in my family will develop breast cancer. It just means that people in my family are more likely to get it.

Of course, the reason for this has to do with my genes. When a cancer runs in a family like this, it often means that only one copy of a tumor suppressor gene is broken.

We've talked about how tumor suppressor genes cause cancer when they stop working. But remember, we have two copies of most of our genes - one from mom and one from dad. If I have one working copy of a tumor suppressor gene and one broken copy, I'm probably OK, because the working copy can pick up the slack.

So why am I at a higher risk for breast cancer? It has to do with how likely I am to develop a mutation in my one good copy, compared to someone who needs to develop mutations in both of her copies. Scientists call this the two-hit hypothesis.

Let's use the tumor suppressor gene BRCA1 as an example. Many women with breast cancer have two broken copies of BRCA1 in their cancer cells.

Most women inherit two normal copies of BRCA1. To get breast cancer, these women have to get mutations in both copies of their BRCA1 gene. Remember, our DNA is over 6 billion letters long and mutations are pretty random in where they hit. So the odds of getting mutations in both copies of our BRCA1 gene aren't very high.

Imagine a game of pin the tail on the donkey. In the game, you are blindfolded and you need to put the tail on the right part of a picture of a tailless donkey. It's hard enough to do once. But twice in a row is even harder.

Donkey party game
Getting mutations in the same place twice is less likely than pinning the tail twice. (Image: Wikimedia Commons)

Now instead of a donkey, imagine a sentence that's 6 billion letters long. And you need to pin the tail in the right set of letters. Twice. Pretty unlikely!

But doing it once is more likely. And this is what happens for women who inherit one broken copy of BRCA1 from their mom or dad. Their donkey has already been pinned once with a tail. These women only need to mutate one copy of BRCA1 to get breast cancer. And getting a mutation in only one copy of a gene is much more likely than getting a mutation in both copies.*

What does all this mean? It means that women who inherit a mutation in their BRCA1 gene have a much greater chance of getting breast cancer (36-85%, compared to about 13% in the general population).

So that's why some people have cancers that run in their families. They inherit a greater risk for cancer because one of their tumor suppressor genes is already mutated. (Even two broken copies of a tumor suppressor gene isn't usually enough to cause cancer. Click here to learn why).

As you can see, cancer is pretty complicated business! Sometimes we inherit broken genes that cause cancer. Sometimes these broken genes just increase the risk of cancer. And sometimes we get cancer because of DNA mistakes that randomly accumulate during our lives.

*How much more likely?

The BRCA1 gene is about 80,000 letters (or nucleotides) long. We have two copies of BRCA1 (one from mom, one from dad), so that's 160,000 letters.

Scientists estimate that as our cells copy their DNA, unfixed DNA mistakes occur in about 1 in every 50 million letters. So the chances of getting a mistake in BRCA1 is 160,000 divided by 50 million, or about 1 in 300 each time a cell copies its DNA. (Most of these mistakes won't actually make a broken BRCA1 protein.) That's the risk for people who inherit one broken copy of BRCA1.

But people who inherit two normal copies of BRCA1 have to develop a mutation in both copies. The odds of that is 1 in 300 times 1 in 300, or 1 in 90,000. That's a lot less likely than 1 in 300! And that's why people who inherit one broken BRCA1 have a much greater risk of breast cancer.

Also, having one broken copy of a tumor suppressor gene like BRCA1 can sometimes make our DNA more fragile. This means that the DNA is more likely to develop mutations. So the risk for people who inherit one broken copy of a gene may be much higher.

Author: Ruth Tennen

When this answer was published in 2007, Ruth was a Ph.D. candidate in the Department of Cancer Biology, studying telomerase regulation in cancer and stem cells in Steve Artandi's laboratory. Ruth wrote this answer while participating in the Stanford at The Tech program.

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