The Strange Mystery of the Cancer Anomaly

The incidence of most cancers increases with age but then mysteriously drops. Now one biomedical engineer has worked out why: some people are immune to cancer

Here’s an interesting puzzle. The common conception is that your risk of cancer starts off small in early life and increases as you get older. So children and young people are less likely to develop the disease than somebody who is middle aged who in turn is less likely to develop cancer than a centenarian.

Not so. Epidemiologists have long known that the incidence of most cancers increases until it reaches a maximum at a certain age and then drops dramatically as people get older. The anomaly is well studied, found all over the world and true for many different types of cancer (see diagrams above).

That raises an important question: how come? After all, cancer is thought to start when a series of genetic alterations accumulate in a cell. These changes prevent ordinary cell functions such as DNA repair and so on and these malfunctions eventually trigger cancerous growth. Clearly, if these changes accumulate over time, the risk of developing the disease must also increase over time.

And therein lies the puzzle, one that has stumped oncologists and epidemiologists alike for years. What could possibly explain the discrepancy between the data and this entirely reasonable model of cancer development?

Today, we get an answer thanks to the work of James Brody a biomedical engineer at the University of California, Irvine. He shows that there is no discrepancy between the data and the model of cancer development provided that one additional assumption is true. This is that the population can be divided into two groups—one group that is susceptible to cancer and a much larger group that is not susceptible to cancer.

To explain how,Brody offers a thought experiment. Imagine a group of people who are observed from birth, as they grow up and as they get old. These people never die but the dates on which they develop cancer are recorded.

If all these people are susceptible to the cancer, they will all be diagnosed at some point. And since the disease is triggered by the accumulation of changes in cells, this is a process that takes time.

Now imagine plotting the incidence of this disease against time. The incidence will be small at first, then increase as more people develop the disease. But after most people have been diagnosed, the incidence will drop and eventually fall to zero, at which point the entire population will be sufferers.

The result is a curve in which the incidence of the disease rises, reaches a maximum and then falls. And the area under the curve, the number of individuals with the disease, should be equal to the entire population.

Now Brody imagines a similar thought experiment. But this time, only twenty per cent of the population are susceptible to the disease. Once again, the incidence of the disease again rises and then falls as people get older and then drops to zero when all the susceptible individuals have succumbed. But the total area under the curve is equal to twenty per cent of the population.

This he says is exactly what happens with cancer in the real world. The reason that the age-related incidence of cancer rises to a maximum and then drops with age is that only a certain portion of the population is susceptible to the disease. And when they’ve all been diagnosed, there’s nobody left who can get it.

By studying the data from real populations, he has been able to work out the size of these populations. With colon cancer, for example, about 12 per cent of the population is susceptible.

“The second subpopulation, consisting of about 78% of the population is immune to developing colon cancer,” he says.

This conclusion implies something even more significant. Brody points out that the data only makes sense if people become members of one group or the other before the age of twenty. So your susceptibility to cancer is determined, one way or the other, in childhood, or more likely, before birth.

That’s not such a strange idea. It’s not the first time that evidence has emerged that an individual’s risk of a certain disease is pre-programmed before birth. In fact the idea has a name: the developmental origin of disease hypothesis.

This hypothesis was originally put forward to explain the observation that areas of the UK that had the highest rates of infant mortality in the early 20th century also had the highest rates of death from coronary heart disease decades later.

The thinking is that environmental conditions in the womb somehow preprogram the body to be more susceptible to certain disease and that this also manifests itself in higher rates of infant mortality and lower birth weights.

And although the mechanism for this process is not understood, epidemiologists have repeatedly gathered similar evidence for it from all over the world.

If Brody is correct, a similar process must be at work in the womb that predisposes people to most types of cancer. The question now, of course, is what could this be and how it can be prevented.

One idea is that epigenetic factors could play a role. Another is that genetic mutations that occur in the womb, perhaps from certain types of screening, could go on to cause cancer later in life. Interestingly, though, Brody says that germ line mutations, which are passed on from parents to children, can be ruled out.

It’s worth mentioning one note of caution here. This kind of statistical evidence is bedevilled with subtleties that seem insignificant but can turn out later to be hugely important. Brody does a good job of handling the obvious alternative hypotheses that might explain the data—things like latent cancers in old people that go undiagnosed, preferential screening effects at certain ages and so on.

So while this work is convincing and interesting, it is by no means a slam dunk. But what it does provide is more reason to investigate the hugely complex developmental processes that go on in the womb and their increasingly important links to illness later in life.

Ref: arxiv.org/abs/1310.8619: The Age Specic Incidence Anomaly Suggests That Cancers Originate During Development