‘Information Theory’ recruited to help scientists find genes for cancer – ScienceDaily

Using a widely known field of mathematics designed primarily to study how digital and other forms of information are measured, stored, and shared, scientists at Johns Hopkins Medicine and Johns Hopkins Kimmel Cancer Center say they have discovered a likely key genetic culprit for developing acute lymphoblastic leukemia ( ALL).

ALL is the most common form of childhood leukemia, affecting about 3,000 children and teens each year in the United States alone.

In particular, Johns Hopkins’ team used “information theory,” applying an analysis that relies on strings of zeros and ones — a binary system of symbols common to computer languages ​​and codes — to identify variables or outcomes of a particular process. In the case of cancer biology in humans, scientists have focused on a chemical process in cells called DNA methylation, in which certain chemical groups bind to areas of genes that run gene on / off switches.

“This study shows how the mathematical language of cancer can help us understand how cells should behave and how changes in that behavior affect our health,” says Andrew Feinberg, Ph.D. Med., MPH, distinguished professor at Bloomberg School of Medicine, Johns Hopkins University, Whiting School of Engineering and Bloomberg School of Public Health. The founder of the field of cancer epigenetics, Feinberg discovered altered DNA methylation in cancer in the 1980s.

Feinberg and his team say using information theory to find cancer trigger genes may be applicable to a wide range of cancers and other diseases.

Methylation is now recognized as one of the ways in which DNA can be altered without changing the genetic code of the cell. When methylation breaks down in such epigenetic phenomena, certain genes are abnormally turned on or off, triggering uncontrolled cell growth or cancer.

“Most people are familiar with genetic changes in DNA, namely mutations that change the DNA sequence. These mutations are like the words that make up a sentence, and methylation is like punctuation in a sentence, providing pauses and stops as we read,” Feinberg says. In search of a new and more efficient way to read and understand epigenetic code altered by DNA methylation, he worked with Dr. John Goutsias, a professor in the Department of Electrical and Computer Engineering at Johns Hopkins University, and Michael Koldobskimy. Med., Pediatrician, oncologist and assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center.

“We wanted to use this information to identify the genes that trigger the development of cancer, even though their genetic code is not mutated,” says Koldobskiy.

The results of the study’s findings, led by Feinberg, Koldobskiy and Goutsias, were published on April 15 in Nature Biomedical Engineering.

Koldobskiy explains that methylation at a particular gene location is binary — methylation or no methylation — and a system of zeros and ones can represent these differences just as they are used to represent computer codes and instructions.

For the study, the Johns Hopkins team analyzed DNA extracted from bone marrow samples from 31 children with newly discovered ALL at Johns Hopkins Hospital and Texas Children’s Hospital. They sequenced DNA to determine which genes throughout the genome were methylated and which were not.

Newly diagnosed leukemia patients have billions of leukemia cells in their body, Koldobskiy says.

By assigning zeros and ones to parts of the genetic code that were methylated or unmethylated, and using information theory concepts and computer programs to recognize methylation patterns, the researchers were able to find genome regions that are consistently methylated in leukemia and cancer-free patients.

They also saw genome regions in leukemia cells that were randomly methylated, compared to the normal genome, a signal to scientists that these sites may be specifically associated with leukemia cells compared to normal.

One gene, called UHRF1, stood out among other gene regions in leukemia cells that had differences in DNA methylation compared to the normal genome.

“It was a big surprise to find this gene because its link to prostate and other cancers has been suggested, but it has never been identified as a trigger for leukemia,” Feinberg says.

In normal cells, the protein products of the UHRF1 gene create a biochemical bridge between DNA methylation and DNA packaging, but scientists have not precisely deciphered how gene modification contributes to cancer.

The experiments of the Johns Hopkins team show that laboratory-grown leukemia cells that lack UHRF1 gene activity cannot self-renew and maintain additional leukemia cells.

“Leukemia cells aim to survive, and the best way to ensure survival is to vary epigenetics in many regions of the genome, so no matter what it tries to kill cancer, at least some survive,” says Koldobskiy.

ALL is the most common childhood cancer, and Koldobskiy says decades of research into different treatments and the sequence of those treatments have helped clinicians cure most of these leukemias, but relapsing disease remains the leading cause of cancer death in children.

“This new approach can lead to more rational ways of targeting the changes that drive this and probably many other forms of cancer,” Koldobskiy says.

The Johns Hopkins team plans to use information theory to analyze methylation patterns in other cancers. They also plan to determine whether epigenetic changes in URFH1 are associated with treatment resistance and disease progression in pediatric leukemia patients.

The new study was funded by the National Institutes of Health National Cancer Institute (R01CA65438), National Institute of Diabetes and Digestive and Kidney Diseases (DP1 DK119129), National Institute for Human Genome Research (R01 HG006282), National Science Foundation (1656201), Scholarship St. Baldrick’s, Unravel Pediatric Cancer and Damon Runyon Cancer Research Foundation.

In addition to Feinberg, Koldobsky, and Goutsias, research associates include Garrett Jenkinson, Jordi Abante, Varenka Rodriguez DiBlasi, Weiqiang Zhou, Elisabet Pujadas, Adrian Idrizi, Raquel Tryggvadottir, Colin Callahan, Challice Bonifant, and Challice Bonifant of Medicine. .