People with cancer are often desperate to know what caused their disease. Was it something they did? Something they could have prevented?

Overall, experts estimate that about 40% of cancers can be explained by known, often modifiable risk factors. Smoking and obesity represent the primary drivers, though a host of other factors — germline mutations, alcohol, infections, or environmental pollutants like asbestos — contribute to cancer risk as well.

But what about the remaining 60% of cancers?

A new analysis suggests that although many of these cases likely have an underlying lifestyle or environmental component, experts still do not fully understand their origin story. And a small but significant number may simply be due to chance.

Here’s what experts suspect those missing causes might be, and why they can be so difficult to confirm.

Possibility 1: Known Risk Factors Contribute More Than We Realize

For certain factors, a straight line can be drawn to cancer.

Take smoking, for instance. Decades of research have helped scientists clearly delineate tobacco’s carcinogenic effects. Researchers have pinpointed a unique set of mutations in the tumors of smokers that can be seen when cells grown in a dish are exposed to the carcinogens present in tobacco.

In addition, experts have been able to collect robust data from epidemiologic studies on smoking prevalence as well as associated cancer risks and deaths, in large part because an individual’s lifetime tobacco exposure is fairly easy to measure.

“The evidence for smoking is incredibly consistent,” Paul Brennan, PhD, a cancer epidemiologist at the World Health Organization’s International Agency for Research on Cancer (IARC), told Medscape Medical News.

For other known risk factors, such as obesity and air pollution, many more questions than answers remain.

Because of the limitations in how such factors are measured, we are likely downplaying their effects, says Richard Martin, PhD, a professor of clinical epidemiology at the University of Bristol, United Kingdom.

Take obesity. Excess body weight is associated with an increased risk of at least 13 cancers. Although risk estimates vary by study and cancer type, according to a global snapshot from 2012, being overweight or obese accounted for about 4% of all cancers worldwide — 1% in low-income countries and as high as 8% in high-income countries.

However, Brennan believes “we have underestimated the effect of obesity [on cancer].”

A key reason, he says, is most studies use body mass index (BMI) to determine whether someone is overweight or obese, but BMI is a poor measure of body fat. BMI does not differentiate between fat and muscle, which means two people with the same height and weight can have the same BMI, even if one is an athlete who eats lean meats and vegetables while the other lives a sedentary life and consumes large quantities of processed foods and alcohol.

On top of that, studies often only calculate a person’s BMI once, and a single measurement can’t tell you how a person’s weight has fluctuated in recent years or across different stages of their life. However, recent analyses suggest that obesity status over time may be more relevant to cancer risk than one-off measures.

In addition, many studies now suggest that alterations to our gut microbes and high blood insulin level — often seen in people who are overweight or obese — may increase the risk of cancer and speed the growth of tumors.

When these additional factors are considered, the impact of excess body fat may ultimately play a much more significant role in cancer risk. In fact, according to Brennan, “if we estimate [the effects of obesity] properly, it might at some point become the main cause of cancer.”

Possibility 2: Environmental or Lifestyle Factors Remain Under the Radar

Researchers have linked many substances we consume or are exposed to in our daily lives — air pollution, toxins from industrial waste, and highly processed foods — to cancer. But the extent or contribution of potential carcinogens in our surroundings, particularly those found almost everywhere at low levels, is still largely unknown.

One simple reason is the effects of many of these substances remain difficult to assess. For instance, it is much harder to study the impact of pollutants found in food or water, in which a given population will share similar exposure levels, vs tobacco, where it is possible to compare a person who smokes a pack of cigarettes a day to a person who does not smoke.

“If you’ve got exposures that are ubiquitous, it can be difficult to discern their [individual] roles,” Martin said. “There are many causes that we [likely] don’t really know because everyone has been exposed.”

On the flip side, some carcinogenic substances that people encounter for limited periods might be missed if studies are not performed at the time of exposure.

“What’s in the body at age 40 may not reflect what you were exposed at age 5 to 10 on the playground or soccer field,” said Graham Colditz, MD, PhD, an epidemiologist and public health expert at Washington University in St. Louis, Missouri. “The technology keeps changing so we can get better measures of what you’ve got exposure to today, but how that relates to 5, 10, 15 years ago is probably very variable.”

In addition, researchers have found that many carcinogens do not cause specific mutations in a cell’s DNA; rather, studies suggest that most carcinogens lead to cancer-promotingchanges in cells, such as inflammation.

“We need to think of how potential carcinogens are causing cancer,” Brennan said. Instead of provoking mutations, potential carcinogens may use a “whole other kind of pathway,” he explained. When, for instance, inflammation becomes chronic, it may spur a cascade of events that ultimately leads to cancer.

Finally, we don’t know much about what causes cancers in low- and middle-income countries. Most of the research to date has been in high-income countries, such the US, Australia, and parts of Europe.

“There’s a real lack of robust epidemiological studies in other parts of the world, Latin America, Africa, parts of Asia,” Marc Gunter, PhD, a molecular epidemiologist at the IARC, told Medscape Medical News.

Possibility 3: Some Cancers Occur by Chance

When it comes to cancer risk, an element of chance may be at play.

Cancer can occur in individuals who have very little exposure to known carcinogens or have no family history of cancer.

“We all know there are people who get cancer who eat very healthy diets, are never overweight, and never smoke,” Gunter said. “Then there are people on the other end of the extreme who don’t get cancer.”

But what fraction of cancers are attributable to chance?

A controversial 2017 study published in Science suggested that, based on the rate of cell turnover in healthy tissues in the lung, pancreas, and other parts of the body, only about one third of cancers could be linked to environmental or genetic factors. The rest, the authors claimed, occurred because of random mutations that accumulated in a person’s DNA — in other words, bad luck.

That study brought on a flood of criticism from scientists who pointed to serious flaws in the work that led the researchers to significantly overestimate the share of chance-related cancers.

The actual proportion of cancers that occur by chance is much lower, according to Brennan. “If you look at international comparisons [of cancer rates] and take a conservative estimate, you see that maybe 10% or 15% of cancers are really chance,” he said.

Whether some cancers are due to bad luck or undiscovered risk factors remains an open question.

But the bottom line is many unknown causes of cancer are likely environmental- or lifestyle-related, which means that, in theory, they can be altered, even prevented.

“There is always going to be some element of chance, but you can modify your chance, depending on your lifestyle and maybe other factors, which we don’t fully understand yet,” Gunter said.

The good news is that when it comes to prevention, there are many ways to modify our behaviors — such as consuming fewer processed meats, going for a daily walk, or getting vaccinated against cancer-causing viruses — to improve our chances of living cancer-free.

And as scientists better understand more about what causes cancer, possibilities for prevention will only grow.

“There is a constant, slow growth [in knowledge] that is lowering the overall risk of cancer,” Brennan said. “We’re never going to eliminate cancer, but we will be able to control it as a disease.”

Diana Kwon is a freelance journalist based in Berlin. She covers health and the life sciences, and her work has appeared in publications such as Scientific American, The Scientist, and Nature. Find her on Twitter @DianaMKwon.

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