Zosia Chustecka

April 28, 2016

NEW ORLEANS — Why does cancer develop, and how much is due to bad luck? A new mathematical model that tackles these questions may give a better picture than previous studies, say the researchers involved.

The new study, carried out by Sven Bilke, PhD, staff scientist in the Genetics Branch of the National Cancer Institute (NCI), and colleagues, shows a clear difference between cancers that have known environmental causes (such as lung cancer in smokers and liver cancer in persons with hepatitis C infection) and those cancers that do not (eg, osteosarcoma).

"Understanding the impact of environmental and cellular factors in causing cancer is important because it will help define the amount of emphasis needed on cancer prevention vs early detection," Dr Bilke commented.

"Also, people often wonder where their cancer came from, and some have feelings of guilt after diagosis, wondering, Am I responsible for my own disease?" he commented at a press briefing here at the American Association for Cancer Research (AACR) 2016 Annual Meeting.

Dr Sven Bilke

There are still reverberations from a study published last year that suggested that cancer was mostly due to the "bad luck" of random mutations. That study led to a huge backlash from an international cancer organization, which declared the message to be misleading and harmful to both research and public health.

"When you say cancer is due to bad luck, everybody throws up their hands and says there is nothing you can do about it," commented Raymond DuBois, MD, PhD, dean of the Medical University of South Carolina, in Charleston. In fact, he continued, there is a lot that can be done. He noted that screening for cervical, colorectal, and breast cancer has had a huge impact on mortality.

"It's a very harmful message to put out, and I think that the authors did not realize the impact it would have," Dr DuBois told Medscape Medical News in an interview.

A second study came out later that essentially reversed the argument, concluding that most cancers are not due to bad luck but are in fact due to environmental factors. That second study received much less publicity.

The new study tackles the same issue of what causes cancer, and the conclusions from this third study are "somewhere in between," said Dr Bois. "Clearly there are some tumors with an accumulation of mutations in the cancer stem cell department which generate the tumor, but there are others, such as lung cancer from smoking and melanoma from UV exposure, where you can modulate the risk.

"This makes sense," Dr DuBois commented at the press briefing, which he moderated. "There are some things that we know cause cancer that we try to avoid or protect ourselves from," he continued, but there are others that differ from this and for which there is no apparent cause — for example, osteosarcoma and pancreatic cancer.

These cancers result from an intrinsic process, Dr Bilke explained, so even "if we avoid all carcinogens, we may still get cancer," he said. This comes back to the "bad luck" hypothesis. But it is for this very reason that cancer screening is so important, he emphasized, so that any abnormalities due to this intrinsic process can be caught early and acted upon.

New Focus on Cancer-Driver Mutations

For their study, Dr Bilke and colleagues at the NCI developed a new mathematical model to reanalyze the data that were used in the original study that was interpreted as showing "bad luck." That study, by Christian Tomasetti, PhD, and colleagues (Science. 2015;347:78-81, abstract) found a correlation between the number of cell divisions in different tissues and the risk of getting cancer in that tissue. The study concluded that about two thirds of variations in cancer risk can be explained by the number of stem cell divisions, which was interpreted as meaning that about 66% of cancer is due to "bad luck."

A subsequent article by Song Wu, PhD, and colleagues (Nature. 2015;529:43-47) questioned that interpretation. It pointed out that the mathematical model the authors of the article in Science had chosen was intrinsically insensitive to changes in the environment that can influence cancer risk and therefore cannot distinguish between environment and accident. When these researchers corrected for that and reanalyzed the data, they concluded that about 90% of cancers have environmental contributions.

However, both of these previous studies analyzed cancer initiation as the elementary process, Dr Bilke noted. Both studies found that cancer incidence rates closely track the number of cell cycles, he pointed out.

Where they differed was in how they chose the baseline that defines the intrinsic cellular, or "bad luck," component of the risk, he said. Consequently, they disagreed on what constitutes excess, environmentally driven cancer risk.

"In our analysis, we studied cancer-driver mutations as opposed to cancer initiation," Dr Bilke explained.

"It is well established that cancer is the consequence of driver mutations, and the immediate impact of environmental as well as accidental factors is mutation, not cancer initiation," he said.

Excess mutations caused by the environment (or the absence of such mutations) should thus be reflected in the mutation rate, with the cancer initiation rate recapitulating that excess in a complex way, he added.

"Our work estimates this mutation rate from the same data the other two studies used by taking into account that different cancer types require a different number of driver mutations to occur. For example, it takes about six mutations on average to initiate colorectal cancer, while only two mutations are sufficient to initiate retinoblastoma," Dr Bilke said.

New Estimates for Environmental Contribution

"In our study, we found that the mutation rate, not cancer incidence, follows a much narrower distribution, largely taking away the possibility for competing interpretations," he said.

"We found that more than 80% of the mutation rate is accidental, with the exception of colorectal, skin, and lung cancer, where a significant excess was detectable," he continued.

"Using our mathematical approach, we found that with the exception of environmental factors, such as smoking, UV radiation, and diet, which are associated with some cancers, in most cases, cancer-driving mutations are largely random, chance occurrences," Dr Bilke said.

"Even in the absence of excessive carcinogens in the environment, mutations still occur and are difficult to prevent," he said, emphasizing that this is why "it is paramount to follow cancer screening recommendations.

"The results of our study do not at all question the carcinogenic role of smoking, diet, and UV radiation in lung, colon, and skin cancer, respectively. Instead it confirms their role by identifying an increased rate of mutation in these cancers compared with baseline, as in the case of lung cancer among smokers," Dr Bilke noted. "Carcinogens remain dangerous and should be avoided."

Dr Bilke illustrated the manner in which various studies fit alongside one another through the use of a graph (see figure). The cancers that are highlighted in blue are the cancers for which there is no known environmental risk; those highlighted in red have known causes. Examples of the latter include lung cancer in smokers, hepatocellular cancer in persons with hepatitis C infection, and colorectal cancer in persons with genetic predisposition (such as Lynch syndrome and familial adenomatous polyposis).

American Association for Cancer Research (AACR) 2016 Annual Meeting: Abstract LB-291, presented April 19, 2016.

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