DNA ‘typos’ may cause 66% of cancer mutations – Futurity

DNA ‘typos’ may cause 66% of cancer mutations
Random, unpredictable DNA copying mistakes account for nearly two-thirds of the genetic changes that cause cancer—far more mutations than those triggered by heredity or by environmental factors like smoking or pollution, a study finds.

The study used a new mathematical model based on DNA sequencing and epidemiologic data from around the world.

The findings do not in any way suggest that we give up on healthy lifestyles and other strategies for minimizing the likelihood of cancer, say the researchers.

“We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations,” says Bert Vogelstein, co-director of the Ludwig Center at Johns Hopkins University’s Kimmel Cancer Center.

The findings do suggest, however, that medical research pay more attention to those “mistake” mutations that occur randomly as cells copy their genetic information—their DNA—when preparing to divide and create new cells.

“Many people will still develop cancers due to these random DNA copying errors,” Vogelstein says, “and better methods to detect all cancers earlier, while they are still curable, are urgently needed.”

Vogelstein and Cristian Tomasetti, assistant professor of biostatistics at the Johns Hopkins Bloomberg School of Public Health, report the findings in the journal Science.

The researchers estimate that 66% of cancer mutations result from copying errors, 29% can be attributed to lifestyle or environment, and the remaining 5% are inherited.

They say their conclusions do not conflict with epidemiologic studies showing that avoiding unhealthy environments and lifestyles can prevent about 40 percent of cancers. But cancer often strikes people who follow all the rules—not smoking, maintaining a healthy diet and weight, avoiding carcinogens—and who have no family history of the disease. That prompts the pained question, “Why me?”

In a previous study, Tomasetti and Vogelstein reported that DNA copying errors could explain why certain cancers in the United States, such as those of the colon, occur more than others, such as brain cancer. In the new research, they addressed a different question: What fraction of mutations in cancer are due to these DNA copying errors?

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

It generally takes two or more critical gene mutations for cancer to start. Tomasetti and Vogelstein used their model to show, for example, that when critical mutations in pancreatic cancers are added together, 77 percent are due to random DNA copying errors, 18 percent to environmental factors, such as smoking, and 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, is different: 65 percent of 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.

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 environment, and the remaining 5 percent are inherited.

Cancer’s metabolism might be a way to kill it

The scientists say their approach is akin to sorting out why “typos” occur in a 20-volume book: being tired while typing, which corresponds to 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 says random DNA errors will only get more important as populations age, prolonging the opportunity for cells to make more and more mistakes.

Funding for the study came from the John Templeton Foundation, the Lustgarten Foundation for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer Research, the Sol Goldman Center for Pancreatic Cancer Research, and the National Cancer Institute.

Source: Johns Hopkins University

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DNA ‘typos’ may cause 66% of cancer mutations – Futurity




Nose swabs could one day detect lung cancer – Futurity

Nose swabs could one day detect lung cancer
New research points to a better way to diagnose lung cancer: a genomic test that could eventually require only a swab of the nose.

Lung cancer is the deadliest form of cancer in the United States and in the world. According to the National Cancer Institute, it accounts for more than a quarter of cancer deaths in this country, killing about 158,000 people in 2016.

Because lung cancer is so lethal, many current and former smokers undergo precautionary CT scans of the chest. These scans can detect small lesions in the lungs that may be an early sign of cancer—but false positives can lead to invasive and unnecessary lung biopsies.

“The idea that we can sample cells from the nose and tell if someone has lung cancer—that is sort of ‘out there,’” says Marc Lenburg, professor of medicine at Boston University School of Medicine. “To sample cells that far from the tumor and still find a genetic signal is really exciting.”

Scanning for lung cancer doesn’t turn up anxiety

The findings build on previous work in the New England Journal of Medicine in which Lenburg and Avrum Spira, professor of medicine, pathology, and laboratory medicine, report that a genomic test they developed could detect lung cancer in a section of the bronchial airway far removed from the tumor. The test, now called Percepta, was acquired by the genomic diagnostics company Veracyte, released that year, and received Medicare approval in late 2016.

During the Percepta test, which is performed at the same time as a bronchoscopy, a doctor uses a small brush to collect cells in the upper bronchial airway. Spira discovered that these cells, while appearing normal, reside in the cancer’s “field of injury” and contain genetic markers that signal a high likelihood of cancer elsewhere in the lung.

The problem is that “there is a subset of people with pulmonary lesions who do not undergo a bronchoscopy as part of their diagnostic workup,” either because the suspicious lesions are very deep in the lung and inaccessible to the bronchoscope or because the patient suffers from other conditions—like heart failure or emphysema—that make a bronchoscopy difficult or dangerous.

But if people with lung cancer have genomic alterations in the cells in the nose too, a nasal swab could potentially serve the same purpose as a bronchial brush.

To explore this possibility, researchers analyzed genomic changes in nasal swabs from patients recruited for the Percepta clinical trials. “We had previously collected the nasal samples,” Spira says, “but we thought that genomic changes in the nose that associate with lung cancer would be more difficult to detect than those found in the bronchial airway.”

Baby nose cells and lung cells are a lot alike

This proved to be true, but recent improvements in computational approaches to genomic data analysis allowed the team to find a lung cancer signal in the nasal samples. They found 535 genes that were expressed differently in the nasal passages of patients who went on to develop lung cancer, but not in patients with benign lesions. Of those genes, 30 were sufficiently distinctive to be useful as a diagnostic biomarker.

The nasal test needs additional testing. “The people in the original study were already at substantially elevated risk for lung cancer,” says Lenburg. “We need to confirm that these results are valid for a wider population.” Nevertheless, the researchers hope that their findings will eventually lead to a widely used test.

“In the short term, we’ll use the nasal biomarker as a diagnostic test for people who have something suspicious on a CT scan of the chest but are not undergoing bronchoscopy,” says Spira. “But eventually, the nasal test could impact a lot more people as a mass screening tool for lung cancer. That’s the really exciting potential.”

The findings appear in the Journal of the National Cancer Institute.

Source: Boston University

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Nose swabs could one day detect lung cancer – Futurity