When you get cancer at a younger age than is typical, this raises the suspicion that there is a genetic predisposition. For male breast cancer the typical age of incidence is in the mid 60s, and so I am 20 years ahead of the curve. That raises the suspicion immediately, so I was referred for genetic counseling and testing. But what lies behind familial cancer?
Familial cancer is cancer that runs in families, and which makes it more likely that members of that family get the disease. Often family members share the same kind or a limited spectrum of cancers. Overall, very few cancers are familial, with the vast majority being sporadic, meaning that they arose in the patient for the first time.
The biological basis for familial cancer is Knudson’s two-hit or multiple hit hypothesis (http://en.wikipedia.org/wiki/Knudson_hypothesis) which says that you need multiple events, such as gene mutations, to get cancer. Families that have a predisposition towards a particular cancer, carry one hit in their germ line, much like they may have shared genes for hair color, eye color or hemophilia. Having this inherited hit does not guarantee that you get cancer, it just makes it much more likely.
The genes responsible for this phenomenon are the tumor suppressors, and they are involved in important cellular processes that regulate the growth of tissues. When they are lost it make it easier for tumors to appear, which is why they are called tumor suppressors. Because humans have two copies of each gene, one from their mom and from their dad, you have a backup, and in most instances you need to lose both before tumors are no longer suppressed. That’s where the two hits come in: one on each of these genes. You can think of it as having two brakes in your car – they both have to fail, before you lose the ability to slow down.
The original proof of this biology was made in the childhood cancer, retinoblastoma (http://en.wikipedia.org/wiki/Retinoblastoma). Kids who get this cancer are often born with one copy of the retinoblastoma gene, RB1 a tumor suppressor, inactivated. In other words, they have one hit already at birth, and so getting the second hit is much more likely. Its like rolling two dice and needing two 6s. The chance of doing it is 1/36. But if you start with one 6, its much more likely, 1 in 6. I was fortunate to do post-doctoral training with Dr. Webster Cavenee who together with Dr. Ray White discovered the RB1 gene and provided the biological proof of the Knudson hypothesis, a major milestone in our understanding of cancer.
Since the finding of RB1, many other tumor suppressors have been identified, including most famously the p53 gene and the BRCA genes. In many sporadic cancer, meaning those that have no inherited component, these genes are also inactivated because cancers need to inactive the brakes to do their thing. But both copies have to become inactivated, and this requires two unlikely events to happen. If you are born with one inactive copy, then of course your odds are much higher of getting cancer. Its like being born on second base, but not in a good way. That’s also why familial cancer often appears earlier in life – being born on second, you get to home plate sooner (again, not in a good way).
OK. So on to genetic counseling and testing. In breast cancer, including in men, the prime suspects for familial predisposition are the BRCA1 and 2 genes (http://en.wikipedia.org/wiki/BRCA_mutation). Before the test, the odds of having a BRCA mutation can be estimated. You can see my probability below using the calculator on the website of Myriad Genetic Laboratories, who perform the BRCA testing (https://www.myriadpro.com/brca-risk-calculator). One key tip off is if you have a lot of cancer, specifically breast cancer, in your family. We don’t have much cancer at all in the family – we are more stroke and heart attack people. But, as the medical geneticist pointed out, my father’s side of the family is not very large and there are not many women there, so it is important to look at it. As you can see my maximum estimate was 6.9%. We did bot the BRCA sequencing and the BART rearrangement test which looks to see whether the genes have become scrambled. Result: negative. This is good news for my brother, and his son. For me it keeps the mystery of my own cancer shrouded, for now.
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