It’s well known that exposure to ultraviolet rays from sunlight can cause melanoma and that smoking is closely linked to lung cancer.
Two Yale University researchers have made strong genetic arguments for these links, as well as for 22 other types of cancer. By looking at which mutations in our genes are likely to cause certain types of cancer, they can determine which are more preventable and which are more related to factors we can’t control, such as cancer. B. aging.
“There’s some sort of signature in the tumor’s genome that tells you what kind of mutations have been introduced into the genome,” said Jeffrey Townsend, a professor of biostatistics at the Yale School of Public Health.
Although this information isn’t new, Townsend said, “We’ve managed to quantify for each site in the genome how much it actually contributes to cancer.” Their study appears in the journal Molecular Biology and Evolution.
Prostate, pancreatic and thyroid cancers and gliomas are the least preventable because the genetic mutations that cause them arise mainly from aging, according to their analysis. Melanoma, lung cancer, and liver cancer are among those most linked to external factors, such as UV rays, smoking, and chemical exposure, they found.
“Our work was really a synthesis of two different methods,” said Jeffrey Mandell, co-author of the study and a graduate student in Yale University’s Department of Computational and Biology Informatics. “The first method is when we look at a certain type of cancer, we have a set of patient tumors, and so for each patient we try to tell what mutational processes are happening in that person.”
Our genes are made up of long chains of nucleotides called A, C, G, and T for adenine, cytosine, guanine, and thymine. Scientists know that a CCC string mutating into CTC is caused by UV light, although Mandell says the “letters” flanking that string also need to be considered.
Their calculations tell them at what rate the mutations are occurring. They then compare the data with which mutations contribute to a specific cancer.
“So we do the calculations to combine those two pieces of information,” Mandell said. “So I would say given where the mutations come from and how important each mutation is, how important is each process? How much does each process contribute to the road to cancer?”
Examination of each type of cancer reveals that multiple mutations are present in each, so the mutation produced by UV light is found in lung cancer, head and neck cancer, and ovarian cancer, among others. But these cancers are not caused by this particular mutation.
Townsend said her work complements traditional studies linking external factors like tobacco and sunlight to cancer. “That’s, I would say, even a different quality of information, because what we’re getting is an actual readout of individual tumors, where we look at the tumor and say, that’s what caused those mutations,” he said. “So it’s a much more direct measurement of what’s causing it than any of these epidemiologies that we’ve been doing for many, many years.”
Townsend said if the technology had been available during the lawsuits against the tobacco industry, “it would have been like a smoking gun. You look into the tumor, you see the signature of the mutation, it’s there. … How would you argue that this is not caused by smoking?”
Townsend also said there are multiple mutations that can be involved in any cancer, but those that cause the cancer are revealed when the genes in the tumor are analyzed. In melanoma, when the genetic mutations are analyzed, it is “clearly clear” that it is UV light that causes the cancer and not some other factor, such as sunscreen, he said.
“For prostate cancer, for example, there’s very little other than these aging mutations that cause each of the major mutations that you see in the cancer,” Townsend said. “So, for prostate cancer in particular, it’s pretty clear that it’s largely mutant through this aging process alone and typically not through other processes.”
Townsend said there is a gene called KRAS that has a high probability of causing cancer if there is a mutation in its DNA. “KRAS causes cancer in many different types of cancers like lung cancer, pancreatic cancer, thyroid cancer… colon cancer,” he said. “But what’s interesting is when you look at how common a particular change is…it happens all the time in lung cancer and rarely, if ever, in pancreatic cancer or colon cancer.”
He also said while smokers who get lung cancer have a mutation in the KRAS gene, non-smokers who get lung cancer tend to have a mutation in another gene.
He added that genetic mutations aren’t the only things that increase cancer risk. Obesity and lack of exercise can also contribute.
Townsend said her work is most relevant to preventing cancer that is the result of external factors and shows how difficult it is to prevent cancer caused by the aging process.
“This result doesn’t tell you how to treat a tumor,” he said. “It doesn’t tell you where to look to treat a tumor. That tells us why you got a tumor. And that’s incredibly important for prevention. And it tells us how much we can attribute these key mutations to UV light — it’s very big — so it should remind us all to avoid overexposure to the sun.”
Mandell said her study will also be helpful for future research.
“One important application of what we’ve done is that we’ve used a set of definitions of mutational processes, all these known mutational processes that are accepted by the broader research community,” he said. “But if you find a new carcinogen, you might say, oh what kinds of mutations does it cause? OK, hook it up to this method and say how much does it contribute to cancer?”
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