A new view of mutations informs disease risk and treatment response | VUMC Reporter

By Bill Snyder

A transcontinental research effort, led by scientists at Vanderbilt University Medical Center and the University of Michigan, is addressing long-standing assumptions about mutations: how often they occur, what causes them, and what happens. overturned the concept of

The team’s findings recently published in the magazine scientific progress, for example, helping to understand why some people respond to cancer immunotherapy and others don’t. The paper also explains why it is important to study large numbers of people of all ages and ancestral backgrounds.

Dr. Alexander Bick, M.D.

“As we age, we acquire more mutations,” says Joshua Weinstock, Ph.D., a postdoctoral fellow at Johns Hopkins and Stanford, and co-corresponding author of the paper, VUMC. Alexander Vic, M.D., said. “This could be a new cause of disease.”

An assistant professor in the Department of Medical Genetics at VUMC, Dr. Vic is best known for studying somatic (non-inherited) mutations in blood stem cells that can lead to explosive clonal proliferation of abnormal cells (hematopoiesis).

This phenomenon is called voltageless clonal hematopoiesis, or CHIP, and can increase the risk of blood cancers and cardiovascular disease.

CHIP mutations occur in the coding regions of the genome, the portions of DNA that code for enzymes and other proteins. What Bick, Weinstock, and their colleagues found was that somatic mutations also frequently occur in noncoding, nonproteinogenic regions.

“People used to think that acquiring mutations was a rarity,” Bick said. “It was unusual for stem cells to have disease-causing mutations…[and]even if there were mutations in stem cells, they were disease-causing. Random.

“But no one has ever really seen this before,” he continued. “Certainly, no one had looked at a large sample set.”

Researchers from more than 40 institutions nationwide participate in the Transomics for Precision Medicine (TOPMed) program sponsored by the National Heart, Lung, and Blood Institute (National Heart, Lung, and Blood Institute), Over 47,000 blood cell genomes were tested. health.

“When you have 50,000 genomes, you can sometimes see patterns that you can’t see when you have only 2,000 genomes,” Vic explained.

“What we found was really surprising,” Vic said. “Acquired mutations that were not congenital are actually quite common” and appear to accumulate with age. “Most people have at least one,” he said. “Most people in their 50s have 20 to 30.”

Mutations differed among people with different ancestral backgrounds and were not entirely random. “They were happening over and over again in very specific places, among different people,” Vic said.

“We found a surprising number of somatic mutations that are unexpectedly common in parts of the genome that are frequently ignored in cancer research,” Weinstock said. “We found that these mutations are associated with blood cell traits and are strongly associated with some inherited gene mutations.”

Genetic mutations that occur in germ cells (eggs and sperms) become part of the DNA of every cell in the offspring’s body and are passed from one generation to the next.

Bick likened inherited mutations to soil, and acquired mutations to seeds that grow in a particular way from that soil. That would explain why somatic mutations occur over and over again in the same place.

Mutations in non-coding regions can control which genes are turned on and which are turned off through a variety of means without altering the DNA.

Eight of the mutations were found to impact blood cell traits, including the number of monocytes, a type of immune cell involved in inflammation.

In addition to potential associations with inflammatory and autoimmune diseases, this finding may be of particular importance in cancer. This is because cancer cells also acquire different noncoding mutations depending on whether they are from New York, Khartoum or Shanghai.

“This finding that these acquired mutations occur differently in people of different ancestry provides new insights into why these very important anticancer drugs have different effects in different people. It opens your eyes,” Vic said.

Furthermore, Weinstock said the study represents “a broader study of human genetics that extends genetic epidemiology to acquired genetic variation in people without cancer.”

Other VUMC members who contributed to this paper are Benjamin Shoemaker, M.D., MSCI Assistant Professor of Medicine, and Dan Roden, M.D., Ph.D., Senior Vice President, Personalized Medicine, MSCI.

This work was supported by a Burroughs Wellcome Foundation Career Award for Medical Scientists, an NHLBI BioData Catalyst Fellowship, and NIH grants HL117626, HL120393, and OD029586. This content is the sole responsibility of the author and does not necessarily represent his official NIH views.

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