Why Do We Get Cancer? What We Know, What We Don't and What We Underestimate

Cancer patients cannot help asking why they developed the disease. What caused it? Was it something they did, or something they could have prevented?

As oncology specialists, we think 40% of all cancers can be explained by known, usually modifiable risk factors—meaning nearly half may be preventable! Smoking and obesity are the leading factors, but many others (germline [inherited] mutations, alcohol, infections and environmental pollutants such as asbestos) increase the risk of developing cancer.

But what do we know about the remaining 60%?

New research suggests that these remaining cancers are probably influenced by underlying lifestyle or environmental factors, but experts still do not understand their actual origins. A small but important number may be attributable to (bad) luck.

Here is what oncology researchers suspect about the still-unknown causes of cancer, and why confirming these suspicions is so difficult.

Possibility 1: Known Risk Factors May Matter More Than We Think

Take smoking, for example. Through decades of research, scientists have clearly established tobacco's carcinogenic effects. Researchers found that cells grown in a dish and exposed to carcinogens in tobacco undergo a distinctive set of mutations also seen in tumors arising in people who smoke.

Experts can also gather strong evidence from epidemiological studies of smoking prevalence and associated cancer risks and deaths, largely because measuring a person's lifetime tobacco exposure is relatively easy.

Paul Brennan, an epidemiologist at the World Health Organization's International Agency for Research on Cancer, says: “The evidence against smoking is incredibly consistent” .

For other known risk factors, such as obesity and air pollution, there are more questions than answers. Richard Martin, Professor of Clinical Epidemiology at the University of Bristol in the United Kingdom, says limitations in measuring these factors probably lead us to underestimate their effects.

Take obesity. Excess weight increases the risk of developing at least 13 cancers. Although estimates vary by study and cancer type, being overweight or obese accounts for approximately 4% of all cancers worldwide—1% in low-income countries and 8% in high-income countries.

Brennan, however, thinks we underestimate obesity's effect on cancer.

He says the main reason is that people use Body Mass Index (VKİ) to assess excess weight, and this is a poor tool that cannot be used to measure body fat. VKİ does not distinguish fat from muscle, meaning an athletic person eating lean meat and vegetables may have the same VKİ as someone of the same height and weight who is sedentary and consumes large amounts of processed food and alcohol.

Moreover, studies looking at VKİ often calculate a person's VKİ only once, and a single measurement does not show how their weight has fluctuated in recent years or at different life stages. Recent analyses suggest that obesity over time may be more strongly associated with cancer risk than a one-time measurement. Many studies also suggest that changes in our gut microbiota and high blood insulin levels—common in obese or overweight people—may increase cancer risk and accelerate tumor growth.

Considering these additional factors, excess body fat may ultimately play a much greater role in cancer risk. Indeed, according to Brennan, “If we could accurately estimate obesity's effects, we might find that it becomes the main cause of cancer.”

Possibility 2: Lifestyle or Environmental Factors Flying Under the Radar

Researchers have linked many substances we consume or encounter daily to cancer. However, the full range and degree of effects of potential carcinogens around us, especially ubiquitous ones, remain largely unknown.

A simple reason is that evaluating many of these substances is difficult. For example, although one can compare a person smoking a pack a day with someone who does not smoke, examining pollutants in water and food in a given population is harder than studying tobacco.

Martin says: “If risk factors are everywhere and we are exposed to them, distinguishing their individual roles may be difficult. There are probably many causes we really do not know about, and everyone is exposed to them” .

Graham Colditz, an epidemiologist and public health specialist at Washington University, says: “People in their 40s may not reflect what they were exposed to on the playground or football field at ages 5 to 10. Technology keeps changing, so we can measure today's exposures better, but their relationship to exposures 5, 10 or 15 years ago was probably very different” .

Researchers also found that most carcinogens do not directly cause specific mutations in a cell's DNA. Instead, they suggest that most cause cancer-promoting cellular changes such as inflammation.

Brennan says: “We need to consider how potential carcinogens cause cancer. Rather than causing mutations, potential carcinogens represent an entirely different type of pathway”. For example, inflammation, when chronic, can promote a sequence of events that ultimately leads to cancer.

Most research to date has been conducted in high-income countries such as the US, Australia and parts of Europe. Consequently, we know little about what causes cancer in low- and middle-income countries. Addressing this gap, Marc Gunter, a molecular epidemiologist at the International Agency for Research on Cancer, points to “a lack of strong epidemiological studies in other parts of the world, in Africa, Latin America and parts of Asia”.

Possibility 3: Some Cancers Arising by Chance

When it comes to cancer risk, (bad) luck may also play a role.

Cancers mostly occur in people exposed to known carcinogens or with a family history of cancer. However, Gunter says: “We all know people who ate very healthily, were never overweight and never smoked, yet developed cancer. There are also people in the opposite situation who do not develop it”.

How Much Cancer Can Be Attributed to Chance?

In 2017, Science published a controversial study suggesting that only about a third of cancers could be linked to environmental or genetic factors, based on cell turnover rates in healthy tissues of the lungs, pancreas and other body sites. For the remainder, the authors claim they arise because of random mutations accumulating in a person's DNA—in other words, bad luck.

The study drew a wave of criticism from scientists who identified serious flaws that led researchers to greatly overestimate the proportion of cancers due to chance. According to Brennan, that proportion is lower. “If you look at international comparisons of cancer rates and make a measured estimate, perhaps 10% or 15% of cancers are really chance”.

Conclusion

Whether some cancers result from bad luck or other undiscovered risk factors remains unanswered.

The real conclusion, however, is that many unknown causes of cancer are most likely linked to lifestyle or environmental factors, meaning that in theory they could be changed or even prevented.

Gunter says: “There will always be some element of (bad) luck, but you can change your odds through your lifestyle and perhaps other factors we do not yet fully understand”.

The good news is that, when it comes to prevention, there are many ways to change our behavior to improve our chances of a cancer-free life—eating less processed meat and food, exercising daily, walking or getting vaccinated against cancer-causing viruses.

As scientists better understand what causes cancer, opportunities for prevention will grow. Cancer is, after all, a group of diseases with a history older than humanity itself. There is steady, gradual growth in knowledge that reduces cancer risk; although we will never eliminate cancer, the day when we can control it as a disease may not be far away.