BIOLOGY

BIOLOGY

-Read the two papers.

-Answer five questions.

Two years ago, Time wrongly reported that “Most cancer is beyond your control.”

The Guardian incorrectly wrote: “Two-thirds of adult cancers largely ‘down to bad

luck’ rather than genes.” And the BBC misleadingly said: “Most cancer types ‘just

bad luck.’” All of these deceptive headlines arose from a widely misinterpreted

study that looked at the role of random chance in initiating cancers. That paper was

itself criticized for a slew of methodological flaws, and spawned more than a

hundred rebuttals.

No, We Can’t Say Whether Cancer Is Mostly Bad Luck

How some media outlets magnified the problems with a controversial new paper

A woman shows her CT scan film in Beijing, China.

ED YONG

MAR 28, 2017 | SCIENCE

Kim Kyung Hoon / Reuters

[1490710143909] As one scientist

wrote on Twitter, “It’s bad luck that

we are misreporting the same thing

twice in two years.”

[1490710218935] Stem cells are the

ones that renew our bodies by

dividing indefinitely.

Its authors are now back with a follow-up, which reads like a weird blend of

doubling-down, clarification, and mea culpa. Although they’ve gone some way

towards addressing the problems of their first paper, their critics still say they’ve

made several of the same conceptual mistakes. And once again, their work has led

to similarly botched headlines.

[1490710143909] Ultimately, this story reveals less

about why people do or don’t get cancers, and more

about how hard it is to talk or think about these

diseases.

*****

In 2015, Cristian Tomasetti from Johns Hopkins Bloomberg School of Public

Health and Bert Vogelstein from the Johns Hopkins Kimmel Cancer Center were

trying to work out why some parts of the body, like the skin or large intestine, are so

much more prone to cancer than others, like the brain or small intestine. By looking

at U.S. data on 31 types of cancer, they found a clue. The lifetime risk of

developing cancer in a particular tissue was strongly correlated with how often the

stem cells [1490710218935] in that tissue divide.

Which made perfect sense. When a cell divides, it has

to duplicate all of its DNA. Every time this happens, it

picks up a few mutations—typos, created when DNA is copied imperfectly. Most of

these mutations are harmless, but some will disrupt crucial genes. And if stem cells

collect enough mutations in the wrong genes, they start dividing uncontrollably,

creating a tumor. So tissues whose stem cells divide more frequently should indeed

be more susceptible to cancer.

That would have been completely uncontroversial, had Tomasetti and Vogelstein

not framed their results in terms of “bad luck.” Some cancer-causing mutations are

inherited, while others are inflicted upon our DNA by environmental risks like

tobacco, sunlight, alcohol, or asbestos. Tomasetti and Vogelstein argued that the

random mutations arising in dividing stem cells represent a third group—distinct

from the other two, more important, and unlikely to be preventable. When they

published their results in the journal Science, they wrote:

“These results suggest that only a third of the variation in cancer risk

among tissues is attributable to environmental factors or inherited

predispositions. The majority is due to “bad luck,” that is, random

mutations arising during DNA replication in normal, noncancerous stem

cells.”

The paper triggered a hailstorm of criticism. Some scientists chastised the

methods. Why did they ignore common cancers like breast and prostate? Why did

they only focus on the U.S.? Others accused the duo of undermining public health.

Many personal choices, from quitting smoking to staying lean, can dramatically

reduce one’s risk of cancers, but why would you bother if you read headlines saying

that these diseases are “largely down to bad luck?”

Such headlines were disastrously wrong. For a start, Tomasetti and Vogelstein

looked at the differences between body parts, not people. Their data explained why

tumors are more likely to strike the bowel than the brain, but not this bowel versus

that one. As oncologist Vinay Prasad tweeted: “[Their] paper does not explain to

cancer patients why they got cancer. [It] explains why cancer doctors get more

colon cancer consults than sarcoma consults.”

Last week, the controversial duo returned with another co-author and a second

paper, which provides more data for their “bad-luck hypothesis.” This time, they

looked at 17 cancers, including breast and prostate. They also went beyond the

U.S., collating data from 69 countries that vary greatly in their cancer rates and

their exposure to environmental risks. And despite that variation, everywhere the

team looked, they found the same strong correlation between a tissue’s cancer risk

and its rate of stem cell divisions.

[1490714059297] Disclosure: I

worked at Cancer Research UK from

2004 to 2011, but have no current

ties to the organization.

[1490713705085] Consider a group

of 10 lung cancer patients. The team

estimates that in four of them, every

cancer-causing mutation was the

result of something environmental. In

one person, every mutation was a

random replication error. And in five,

there was a mix. So even though 35

percent of mutations were randomly

acquired, 90 percent of cases were

preventable.

[1490713639784] Some types of

mutations are clearly the work of, say,

sunlight or tobacco carcinogens. But

most are impossible to assign to a

specific cause. So here’s what you

can do instead. Let’s say you find

that lung cancer patients who have

never smoked have 100 mutations

on average, while smokers have

300. You deduce that two-thirds of

the mutations in the smokers are due

to smoking, and the rest are

probably due to replication errors.

That’s what the team did, using data

on mutation rates from tumor-

sequencing projects, and data on

cancer risk factors from

epidemiological studies.

Next, they used data from tumor-sequencing projects and epidemiological studies

to sort cancer-causing mutations into three buckets [1490713639784] , depending on

their origin. Overall, they calculated that 66 percent

of cancer mutations are due to random, unavoidable

replication errors (R), 29 percent are due to

environmental factors (E), and 5 percent are inherited

(H). But those proportions vary a lot between cancers:

in lung cancer, just 35 percent of mutations are

randomly acquired, compared to 77 percent for

pancreatic cancer.

But the team have clearly emphasized that these

numbers don’t tell us what proportion of cancers are

preventable. It can take several mutations to trigger a

case of cancer, so even if one of those was due to an

avoidable environmental factor, that cancer could

still have been prevented [1490713705085] . That’s

why, as the team stressed, their finding that 66

percent of mutations are randomly acquired is totally

consistent with other estimates that 42 percent of

cancer cases are preventable. Mutations don’t equate

to cases.

Try telling that to the Daily Mail, Sun, and Forbes,

which all ran headlines ascribing the majority of

cancer cases to bad luck. The British charity

[1490714059297] Cancer Research UK made the same

error in a (since-corrected) post describing the team’s

work. Stat avoided that pitfall, but when Scientific

American reprinted their story, they bowdlerized the

headline into “Most Cancer Cases Arise from ‘Bad

Luck.’” Most egregiously, The Daily Telegraph said “Two thirds of cancers are

unavoidable even if you live a healthy life.”

As for the paper itself, “it’s certainly more balanced than their earlier one,” says

Rebecca Siegel, an epidemiologist at the American Cancer Society, “but it seems to

me that they’re still missing the boat.”

For Siegel, it comes down to how you interpret the so-called R-mutations—the ones

that supposedly arise during normal DNA replication. Imagine a group of rapidly

dividing stem cells. Sure, on their own, they would spontaneously develop a lot of

random cancer mutations. But they would also amplify any mutations they picked

up from an environmental trigger, producing many daughters that carried the same

scars. Both routes produce the same pattern—greater cancer risk in more rapidly

dividing cells—but only in the former are mutations initiated by unlucky stem cells.

In the latter, they are secretly environmental in origin. For similar reasons, it seems

weird to divide mutations into heritable ones, environmental ones, and replication

errors. All three categories are deeply connected. An inherited mutation might

hobble a cell’s ability to repair typos in its DNA, while an environmental trigger

might make the cell divide more rapidly. Both events would increase the frequency

of replication errors.

But Tomasetti actually agrees. He has defined the R-mutations as those that occur

in a normal tissue that’s not beset by anything else; if a mutation is caused by extra

replication due to an environmental trigger, he puts it in the E bucket. The R-

mutations represent the absolute baseline, in a hypothetical world where no

carcinogens or cancer genes exist.

Still, Song Wu, a statistical geneticist at Stony Brook University, says that

Tomasetti’s team has likely overestimated the proportion of R-mutations. They first

estimated the proportion of mutations caused by known cancer genes, and known

environmental risk factors—and subtracted those from the total. The rest, they say,

are R-mutations. But that’s only true if we think we already know everything about

the genes and risk factors that lead to cancer, “and I doubt anyone working in

cancer believes that’s even close to the truth,” says Wu. For example, virtually

every case of cervical cancer is caused by a virus called HPV. If this study had been

done before HPV was discovered, it would have concluded that almost all cervical

cancer mutations were R-mutations, and that the disease wasn’t preventable. As it

is, we have a vaccine for it.

“We can’t use things that are unknown,” counters Tomasetti. “If new

environmental factors will be discovered,” maybe the daunting 66 percent figure

will go down. Then again, it could also go up since the Western population is ageing

(and age brings even more stem cell divisions), and since public health policies

might reduce the contribution of environmental factors.

Wu and others argue that Tomasetti hasn’t even taken account of known unknowns

—sources of environmental risk that are clearly present, but still undefined.

Consider prostate cancer. The team calculated that a whopping 95 percent of

prostate cancer mutations are R-mutations, which would make the disease almost

entirely unpreventable. “That just doesn’t make sense,” says Yaniv Erlich, a

geneticist at Columbia University and the New York Genome Center. There are

substantial differences in prostate cancer rates between different countries. If the

disease was mainly caused by random replication errors, rates should be the same

everywhere you look—and they clearly aren’t. Indeed, immigrants who move from

countries with low rates to those with high ones tend to pick up the higher risk of

their new homes. The environment clearly matters for prostate cancer; it’s that we

don’t yet know which factors are important. “The ‘environment’ is inherently

harder to study than [inherited] mutations or replicative errors,” says Clarice

Weinberg, a statistician at the National Institute of Environmental Health

Sciences. “We know quite a lot about carcinogenic effects of smoking, obesity and

certain occupational exposures, but not much about other environmental factors

experienced during life or prenatally.”

The rates of the other common Western cancers—breast, lung, prostate, and

colorectal—also vary considerably between countries. Many others, including

thyroid, kidney, and liver cancers, have seen their rates increase over time. Yet

others are substantially influenced by known risk factors: The majority of

esophageal cancers are caused by tobacco and alcohol, while most skin cancers are

caused by sun exposure. All of this argues against the dominance of R-mutations in

fueling cancer. Tomasetti’s papers are based on mathematical models—interesting,

but we need to gauge their claims against the reality of hundreds of epidemiological

studies. “Their hypothesis just doesn’t jive with epidemiological evidence that we

know to be true,” says Siegel.

And even if a particular cancer is entirely caused by R-mutations, it might not be

unpreventable, as sites like Smithsonian and NPR have reported. Aspirin, that most

familiar of drugs, might help to reduce the risk of colorectal cancer, as well as other

types like esophageal and pancreatic. Some scientists are looking to drugs like

aspirin as ways of halting the evolution of cancer, by reducing the rate at which

mutations occur in the first place. And as cancer scientists move beyond their

traditional focus on mutated genes, it may become possible to prevent tumors by

targeting surrounding cells, reducing inflammation, or stimulating the immune

system.

In fairness, Tomasetti’s group say in their paper that “R mutations appear

unavoidable now, but it is conceivable that they will become avoidable in the

future,” and he told me on the phone that “this is definitely something we should

focus our research on.” But Erlich is concerned that exactly this kind of research

will be stymied by the focus on dominant and supposedly unavoidable R-

mutations. “I think it’s unfortunate,” he says. “This is a high-profile paper by

famous people in the field. Others will look at this and say: This is the endpoint in

the war against cancer?”

The odd thing about the two papers is that, for all their controversy, they don’t

seem very radical. As Otis Brawley, chief medical officer for the American Cancer

Society, told CNN: “[It] doesn’t tell me anything I hadn’t known for the last 20

years.” “I think it’s very well-known that chance plays a role,” adds Siegel. “If you

look at lung cancer, we know that 80 percent of U.S. cases are to do with smoking,

but only 20 percent of smokers develop lung cancer. Chance is a huge factor.”

But Tomasetti argues that chance is understated. “You can check the website of any

major institution, and there’s no mention of this,” he says. “I’m not claiming that

66 percent is the right number, but this is a component that was rarely mentioned

and never measured. And it’s here to stay.”

If that’s the case, we had better improve in how we talk about it. The “bad luck”

rhetoric is unhelpful, especially when it’s equated with “replicative errors”.

Ultimately, it all comes down to luck. Puff on a cigarette and the carcinogens within

may or may not disrupt an important gene. If you inherit a gene that predisposes

you to cancer, you may or may not develop the disease—even the highest-risk genes

are not guarantees. Cancers are all about probabilities, and this is one of the hardest

things about the diseases to convey. You can do everything “wrong” and slip

through the net. You can do everything “right” and still get come up short.

Tomasetti and Vogelstein have said that they hope to alleviate the guilt felt by

patients—and especially parents of children with cancer—who read that many

cancers are preventable and feel that they’re to blame for their poor health. That is

a noble goal, but there’s also a risk of demotivating people who could do something

about their cancer risk. This is one of the two great challenges of cancer

communication: walking the fine line between empowerment and guilt, between

hope and despondence.

The other challenge lies in going from the abstract world of statistical models and

population-wide studies to the concrete world of individuals and patients. In

reporting the recent paper, CNN wrote that “bad luck mutations increase cancer

risk more than behavior” and that “dumb luck plays a more significant role than

either environmental, lifestyle or hereditary factors in causing this disease.” That’s

arguably accurate when you’re talking about mutations in a statistical model. But

readers will look at that and think about themselves in their daily lives. They’ll hear

that their personal cancer risk is determined more by the vagaries of fate than by

their own choices. And they’d be wrong to do so.

I can rattle off statistics about what proportion of lung cancers are caused by

smoking versus other causes, or what proportion of mutations are environmental,

hereditary, or otherwise. But I cannot tell someone whether their cancer was down

to the wrong carcinogen hitting the wrong gene, or random errors in a dividing

stem cell. That fundamental, heartbreaking, existential question—Why me?—has

no answer.

ABOUT THE AUTHOR

ED YONG is a staff writer at The Atlantic, where he covers science.

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