cancer mutations

Scientists Unveil Enzymes Driving Cancer Mutations

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DNA sequence with colored letters on black background containing mutation

Researchers at the University of California, Irvine (UCI), have uncovered the significant roles of two enzymes, APOBEC3A and APOBEC3B, in creating mutations within cancer genomes, opening up new avenues for developing targeted intervention strategies in cancer treatment.

Reporting in Nature Communications, the study highlights how these enzymes modify the DNA in tumor cells, leading to mutations associated with a worse prognosis for patients.

“It’s critical to understand how cancer cells accumulate mutations leading to hot spots that contribute to disease progression, drug resistance and metastasis,” said Rémi Buisson, the study’s corresponding author and an assistant professor of biological chemistry at UCI.

“Both APOBEC3A and APOBEC3B were known to generate mutations in many kinds of tumors, but until now we did not know how to identify the specific type caused by each. This finding will allow us to develop novel therapies to suppress mutation formation by directly targeting each enzyme accordingly.”

For their research, the team used a novel method to characterize the DNA sequences targeted by the enzymes, discovering that APOBEC3A and APOBEC3B do not recognize the same DNA sequences and structures within cancer genomes—a revelation that could lead to more personalized treatments.

The enzymes in question are known for their role in catalyzing the conversion of cytosine to uracil bases in the DNA—a process that can lead to harmful mutations in cells. Interestingly, in the experiments APOBEC3A showed a preference for single-stranded DNAs, especially those forming stem-loop secondary structures, while APOBEC3B selectively targeted distinct DNA stem-loop structures.

The study introduces “Oligo-seq,” an in vitro sequencing-based method that identifies specific sequence contexts that promote APOBEC3A and APOBEC3B activity. Using this method, the researchers were able to demonstrate that the base-conversion activity of these enzymes is highly influenced by the sequences surrounding the targeted base, as well as the structural features of APOBEC3B and APOBEC3A responsible for their substrate preferences.

The researchers believe, that the discovery that APOBEC3A and APOBEC3B generate distinct mutation landscapes in cancer genomes based on their unique substrate selectivity has vast implications, paving the way for developing novel therapies that could prevent these mutations from forming, potentially suppressing tumor evolution and improving patient outcomes.

“The next steps are to investigate whether mutations caused by these enzymes lead to various types of therapy resistance. It’s also critical to identify molecules that inhibit APOBEC3A and APOBEC3B to prevent mutations from forming,” Buisson explained, offering hope for more effective cancer therapies that can suppress mutation formation and, consequently, slow disease progression.

New study sheds light on why cancer often strikes those with healthy lifestyles.

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Most cancer mutations are due to random DNA copying ‘mistakes,’ not inherited or environmental factors, Johns Hopkins researchers say

A new study by scientists at Johns Hopkins provides evidence that random, unpredictable DNA copying “mistakes” account for nearly two-thirds of the mutations that cause cancer.

The researchers say their conclusions are supported by epidemiologic studies showing that approximately 40 percent of cancers can be prevented by avoiding unhealthy environments and lifestyles. But among the factors driving the new study, they add, is that cancer often strikes people who follow all the rules of healthy living—nonsmoker, healthy diet, healthy weight, little or no exposure to known carcinogens—and have no family history of the disease, prompting the pained question, “Why me?”

ACROSS THE 32 CANCER TYPES STUDIED, THE RESEARCHERS ESTIMATE THAT 66 PERCENT OF CANCER MUTATIONS RESULT FROM COPYING ERRORS, 29 PERCENT CAN BE ATTRIBUTED TO LIFESTYLE OR ENVIRONMENTAL FACTORS, AND THE REMAINING 5 PERCENT ARE INHERITED.

“It is well-known that we must avoid environmental factors such as smoking to decrease our risk of getting cancer. But it is not as well-known that each time a normal cell divides and copies its DNA to produce two new cells, it makes multiple mistakes,” says Cristian Tomasetti, assistant professor of biostatistics at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health. “These copying mistakes are a potent source of cancer mutations that historically have been scientifically undervalued, and this new work provides the first estimate of the fraction of mutations caused by these mistakes.”

Adds Bert Vogelstein, co-director of the Ludwig Center at the Kimmel Cancer Center: “We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations. However, many people will still develop cancers due to these random DNA copying errors, and better methods to detect all cancers earlier, while they are still curable, are urgently needed,”

Tomasetti and Vogelstein’s research will be published Friday in the journal Science.

Current and future efforts to reduce known environmental risk factors, they say, will have major impacts on cancer incidence in the U.S and abroad. But they say the new study confirms that too little scientific attention is given to early detection strategies that would address the large number of cancers caused by random DNA copying errors.

“These cancers will occur no matter how perfect the environment,” Vogelstein says.

In a previous study authored by Tomasetti and Vogelstein in the Jan. 2, 2015, issue of Science, the pair reported that DNA copying errors could explain why certain cancers in the U.S., such as those of the colon, occur more commonly than other cancers, such as brain cancer.

Cristian Tomasetti (left) and Bert Vogelstein

Image caption:Cristian Tomasetti (left) and Bert Vogelstein

In the new study, the researchers addressed a different question: What fraction of mutations in cancer are due to these DNA copying errors?

To answer this question, the scientists took a close look at the mutations that drive abnormal cell growth among 32 cancer types. They developed a new mathematical model using DNA sequencing data from The Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database.

According to the researchers, it generally takes two or more critical gene mutations for cancer to occur. In a person, these mutations can be due to random DNA copying errors, the environment, or inherited genes. Knowing this, Tomasetti and Vogelstein used their mathematical model to show, for example, that when critical mutations in pancreatic cancers are added together, 77 percent of them are due to random DNA copying errors, 18 percent to environmental factors (such as smoking), and the remaining 5 percent to heredity.

In other cancer types, such as those of the prostate, brain, or bone, more than 95 percent of the mutations are due to random copying errors.

Lung cancer, they note, presents a different picture: 65 percent of all the mutations are due to environmental factors, mostly smoking, and 35 percent are due to DNA copying errors. Inherited factors are not known to play a role in lung cancers.

Looking across all 32 cancer types studied, the researchers estimate that 66 percent of cancer mutations result from copying errors, 29 percent can be attributed to lifestyle or environmental factors, and the remaining 5 percent are inherited.

The scientists say their approach is akin to attempts to sort out why “typos” occur when typing a 20-volume book: being tired while typing, which represents environmental exposures; a stuck or missing key in the keyboard, which represent inherited factors; and other typographical errors that randomly occur, which represent DNA copying errors.

“You can reduce your chance of typographical errors by making sure you’re not drowsy while typing and that your keyboard isn’t missing some keys,” Vogelstein says. “But typos will still occur, because no one can type perfectly. Similarly, mutations will occur, no matter what your environment is, but you can take steps to minimize those mutations by limiting your exposure to hazardous substances and unhealthy lifestyles.”

Tomasetti and Vogelstein’s 2015 study created vigorous debate from scientists who argued that their previously published analysis did not include breast or prostate cancers, and it reflected only cancer incidence in the United States.

Tomasetti and Vogelstein now report a similar pattern worldwide, however, supporting their conclusions. They reasoned that the more cells divide, the higher the potential for so-called copying mistakes in the DNA of cells in an organ. They compared total numbers of stem cell divisions with cancer incidence data collected by the International Agency for Research on Canceron 423 registries of cancer patients from 68 countries other than the United States, representing 4.8 billion people, or more than half of the world’s population. This time, the researchers were also able to include data from breast and prostate cancers. They found a strong correlation between cancer incidence and normal cell divisions among 17 cancer types, regardless of the countries’ environment or stage of economic development.

Tomasetti says these random DNA copying errors will only get more important as societies face aging populations, prolonging the opportunity for our cells to make more and more DNA copying errors. And because these errors contribute to a large fraction of cancer, Vogelstein says that people with cancer who have avoided known risk factors should be comforted by their findings.

“It’s not your fault,” says Vogelstein. “Nothing you did or didn’t do was responsible for your illness.”

In addition to Tomasetti and Vogelstein, Lu Li, a doctoral student in Tomasetti’s laboratory in the Department of Biostatistics at the Johns Hopkins Bloomberg School of Public Health, also contributed to the research.

Watch the video discussion. URL:https://youtu.be/R4rxlRsNcs8

Source:http://hub.jhu.edu

Two thirds of cancer mutations result from completely random DNA mistakes

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An increased focus on early detection will be needed to effectively treat the disease

a yellow breast cancer cell on a red background

A breast cancer cell, photographed by a scanning electron microscope, which produces a 3-dimensional images.

Humans have forever questioned what causes human cancer. And we’ve come a long way: Early theories proposed by Hippocrates in the middle ages suggested the disease arose from supposed “black bile” accumulating in the body. This and other subsequent theories—like cancer cells themselves as infectious, contagious agents—have been debunked by modern research. Scientists now understand cancer arises from mutations created in our DNA when cells replicate and three factors cause those mutations: Environmental, hereditary, and random ones. However, the influence of one of those factors over another is still largely unknown.

Now, a group of researchers at The Johns Hopkins University used new statistical models to figure this out. After analyzing 32 common cancer types, the researchers estimate that 66 percent of cancer mutations are from random ones that occur when cells divide, 29 percent from environmental factors, and 5 are inherited. This means that for people with these cancers, about two thirds of all mutations that eventually result in cancer happen not because of factors in their environment or what they inherit from their parents, but rather as a direct result of how healthy cells grow and divide. The geneticists say researchers should use this new understanding to focus more efforts to detect and treat cancer as early as possible.

 

Dividing Breast Cancer Cell

Cell division, in which one cell breaks apart into two cells in an effort to create new, needed healthy ones, is a natural process. But as this occurs, random mutations happen to the DNA within the cells. Other factors can cause these mutations, too. Environmental ones like smoking or eating a diet low in fiber increase the rate that these errors occur. When enough of these mutations accumulate—no matter what their cause—that’s when the cells begin dividing uncontrollably. That uncontrolled division is what we call cancer.

The researchers wanted to know how much of an influence each mutation-causing factor had on the occurrence of cancer. For 32 cancer types, they pulled together medical information from patients around the world, including those patients’ DNA sequences, information about their lifestyle, and what type of cancer they had. They combined these data sets to understand the influence of each mutation factor. Here’s how one analysis, for lung cancer, would go: Researchers already know the average number of random mutations that happen to an otherwise healthy person who eats well and never smokes. Say that number is 100. From those data sets, and from previous research, they found smokers have cell mutation rates that are three times higher than healthy, non-smokers. So you would expect to find 300 mutations in smokers. So, probabilistically, you can attribute that extra 200 to smoking. They did a similar analysis for 31 other cancers by comparing the mean number of mutations from healthy individuals to mutations attributed to known environmental and heritable causes of those cancers.

 Comparing the 32 types of cancers further demonstrated the effect random mutations have. Cancer is more common in tissues that divide often. For example, cells in the colon divide much more frequently than cells in the brain, which is why colon cancer is much more common in the population than brain cancer is. But overall, the numbers they got—66 percent random, 29 percent environmental, and 5 percent inherited—told the researchers that a majority of cancers occur from random, unpredictable “mistakes” that can’t be predicted.

causes of cancer in the body

DNA mutations, which ultimately cause cancer, result from three causes: they’re inherited, they happen randomly as cells divide, or they occur due to environmental factors like smoking. Researchers found that the cause is different for each organ, charted above. Lung cancer, for example, has a larger percentage of environmental mutations because of smoking whereas brain cancer is almost entirely a result of random errors stated in the graph as “Replicative”.

It offers comfort to the millions of patients who have developed cancer but have led near perfect lives, says Bert Vogelstein, a co-author of the study and professor of pathology and oncology at Johns Hopkins. “We want it to help people avoid feeling guilty about their cancers. These cancers would have occurred not matter what they did.” The researchers say the results could also help guide future research: Understanding how to recognize cancer early on, when its first developing, could offer a better chance at successfully treating it.

So is there anything we can do to slow down, or even completely eliminate these random mutations? Right now, the researchers say most are unavoidable, but it may be possible that some of them could become avoidable in the future. There are four ways that cells randomly mutate during cell division. One of them, called reactive oxygen species or “free radicals” could theoretically be reduced by exposing cells to special antioxidants. Vogelstein says a better understanding of these mutations could open up areas of research to develop these kinds of antioxidant preventative therapies. “It’s similar to our understanding of cholesterol,” Vogelstein says. “Before we knew about cholesterol, we didn’t know we could try to lower it to prevent cardiovascular disease.”

And perhaps this type of research couldn’t come soon enough. The researchers think that in the future, as populations continue to age, the percent of cancer cases attributable to random mutations is only going to increase. As bodies get older, their cells will have experienced more division, which increases the chances of mutations and cancer. Vogelstein says the way we are going to keep up with this increase is finding better ways to detect cancer in its early stage.

Two thirds of cancer mutations result from completely random DNA mistakes

Posted by

0


An increased focus on early detection will be needed to effectively treat the disease

a yellow breast cancer cell on a red background

A breast cancer cell, photographed by a scanning electron microscope, which produces a 3-dimensional images.

Humans have forever questioned what causes human cancer. And we’ve come a long way: Early theories proposed by Hippocrates in the middle ages suggested the disease arose from supposed “black bile” accumulating in the body. This and other subsequent theories—like cancer cells themselves as infectious, contagious agents—have been debunked by modern research. Scientists now understand cancer arises from mutations created in our DNA when cells replicate and three factors cause those mutations: Environmental, hereditary, and random ones. However, the influence of one of those factors over another is still largely unknown.

Now, a group of researchers at The Johns Hopkins University used new statistical models to figure this out. After analyzing 32 common cancer types, the researchers estimate that 66 percent of cancer mutations are from random ones that occur when cells divide, 29 percent from environmental factors, and 5 are inherited. This means that for people with these cancers, about two thirds of all mutations that eventually result in cancer happen not because of factors in their environment or what they inherit from their parents, but rather as a direct result of how healthy cells grow and divide. The geneticists say researchers should use this new understanding to focus more efforts to detect and treat cancer as early as possible.

 Cell division, in which one cell breaks apart into two cells in an effort to create new, needed healthy ones, is a natural process. But as this occurs, random mutations happen to the DNA within the cells. Other factors can cause these mutations, too. Environmental ones like smoking or eating a diet low in fiber increase the rate that these errors occur. When enough of these mutations accumulate—no matter what their cause—that’s when the cells begin dividing uncontrollably. That uncontrolled division is what we call cancer.

The researchers wanted to know how much of an influence each mutation-causing factor had on the occurrence of cancer. For 32 cancer types, they pulled together medical information from patients around the world, including those patients’ DNA sequences, information about their lifestyle, and what type of cancer they had. They combined these data sets to understand the influence of each mutation factor. Here’s how one analysis, for lung cancer, would go: Researchers already know the average number of random mutations that happen to an otherwise healthy person who eats well and never smokes. Say that number is 100. From those data sets, and from previous research, they found smokers have cell mutation rates that are three times higher than healthy, non-smokers. So you would expect to find 300 mutations in smokers. So, probabilistically, you can attribute that extra 200 to smoking. They did a similar analysis for 31 other cancers by comparing the mean number of mutations from healthy individuals to mutations attributed to known environmental and heritable causes of those cancers.

 Comparing the 32 types of cancers further demonstrated the effect random mutations have. Cancer is more common in tissues that divide often. For example, cells in the colon divide much more frequently than cells in the brain, which is why colon cancer is much more common in the population than brain cancer is. But overall, the numbers they got—66 percent random, 29 percent environmental, and 5 percent inherited—told the researchers that a majority of cancers occur from random, unpredictable “mistakes” that can’t be predicted.

causes of cancer in the body

DNA mutations, which ultimately cause cancer, result from three causes: they’re inherited, they happen randomly as cells divide, or they occur due to environmental factors like smoking. Researchers found that the cause is different for each organ, charted above. Lung cancer, for example, has a larger percentage of environmental mutations because of smoking whereas brain cancer is almost entirely a result of random errors stated in the graph as “Replicative”.

It offers comfort to the millions of patients who have developed cancer but have led near perfect lives, says Bert Vogelstein, a co-author of the study and professor of pathology and oncology at Johns Hopkins. “We want it to help people avoid feeling guilty about their cancers. These cancers would have occurred not matter what they did.” The researchers say the results could also help guide future research: Understanding how to recognize cancer early on, when its first developing, could offer a better chance at successfully treating it.

So is there anything we can do to slow down, or even completely eliminate these random mutations? Right now, the researchers say most are unavoidable, but it may be possible that some of them could become avoidable in the future. There are four ways that cells randomly mutate during cell division. One of them, called reactive oxygen species or “free radicals” could theoretically be reduced by exposing cells to special antioxidants. Vogelstein says a better understanding of these mutations could open up areas of research to develop these kinds of antioxidant preventative therapies. “It’s similar to our understanding of cholesterol,” Vogelstein says. “Before we knew about cholesterol, we didn’t know we could try to lower it to prevent cardiovascular disease.”

And perhaps this type of research couldn’t come soon enough. The researchers think that in the future, as populations continue to age, the percent of cancer cases attributable to random mutations is only going to increase. As bodies get older, their cells will have experienced more division, which increases the chances of mutations and cancer. Vogelstein says the way we are going to keep up with this increase is finding better ways to detect cancer in its early stage.

Source:http://www.rawstory.com