Ever wondered why two smokers who smoke the same amount end up with one having cancer and the other does not? What does it actually mean when doctors say that you are “predisposed” to a certain form of cancer?

A famous researcher named Alfred Knudson came up with an answer for that question in the 1970s called the two-hit hypothesis. But before we can understand his theory, it’s important to understand some basic genetic concepts. First, what exactly is cancer? We know it’s a terrible disease, but what's going on inside of your body when you have cancer?

Our body has a whole is made up of tiny units called cells that work together to form our different organs (heart, lungs, kidneys, etc.) which, in turn, work together as one big unit. That’s what keeps us alive. And during our lifetime, most of our cells will multiply so we can have bigger organs or simply replace the older cells. You can imagine how complex of a process the whole thing is and that it requires very tight regulation to make sure that everything goes off without a hitch. It's pretty amazing that we get it right most of the time in the first place!

As it turns out, we have genes that are there specifically to prevent cells from multiplying when they are not supposed to, and we have yet others that tell cells to multiply only at specific times. These genes that regulate cell division fall into multiple categories, but for simplicity's sake, we'll put them in two categories and call them tumor suppressors and oncogenes. The core of the matter is this: when these genes are damaged in any way, there is nothing to tell the cells to stop multiplying. It’s a perpetual green light from there. Cells growing in an uncontrollable manner lead to chaos, and this is precisely what we call cancer!

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When we are born, we roughly get half of our DNA (genes) from our mom and the other half from our dad. We generally have two copies of each gene (one from mom and one from dad). It works in the same way for oncogenes and tumor suppressor genes (meaning we get a copy from each parent).

But unfortunately, sometimes you can get a defective or mutated copy from mom or from dad. When that happens, it doesn’t automatically mean that you’ll get cancer. It just means that now the single gene is going to have to do the job of two. In most cases, this is fairly doable. It might not be as efficient, but it can happen. But what happens when, let’s say, you are born with one functioning gene (oncogene, tumor suppressor or another critical gene) and some external or environmental factor (smoking, chemical exposure, etc.) causes the remaining functional gene to be mutated and stop working? The answer is that you will be left with no functioning genes at all, and that will ultimately lead to cancer.

But what if you were born with two normally functioning genes (again, those same critical genes) and then get exposed to an external/environmental factor? Well, depending on the severity of the external/environmental factor, you can be left with either one functioning gene (in which case you might not develop cancer) or two damaged genes (leading to cancer). This is the underlying principle behind the two-hit hypothesis: you need a double assault affecting both genes to lead to cancer. However, if you’re already born with a non-functioning gene, you become much more susceptible to a particular cancer because you are only one "hit" away from having no functioning protective genes. This is in essence what it means to be more prone to a cancer than other people and can explain why people with similar lifestyles have different cancer outcomes.

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