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Monday, October 25, 2021

University of California-San Diego researchers help map how cancer mutations affect proteins

Researchers at the University of California, San Diego (UCSD) and the University of California, San Francisco (UCSF) have mapped out how hundreds of mutations involved in two types of cancer affect the activity of isolated groups of proteins. .

The work suggests ways to identify new precision treatments that may skirt the common side effects with current chemotherapy.

The effort, known as the Cancer Cell Mapping Initiative (CCMI), was led by Professor Trey Idecker of the UCSD School of Medicine and Moors Cancer Center, and Nevan Crogan, director of the UCSF’s Quantitative Biosciences Institute, who co-authored the study.

The papers were published in the online issue of Science on Friday.

“The key is that we’re moving the conversation about cancer from individual genes to whole protein complexes,” Idecker said. “Over the years, different groups have been discovering more and more mutations associated with cancer, but with so many different genes that scientists cannot explain them all.

“We are now able to explain these mutations at the next level – by looking at how mutations in different genes in different patients affect the same flow in the same protein machines.” “This is the first map of cancer from protein complex lenses.”

DNA contains instructions for making proteins, which then interact with other proteins, almost always in large groups called complexes.

These protein complexes, in turn, make up most of the cell’s machinery, indicating whether the cell’s basic functions, such as feeding, growth, and cell, turn into cancer. If there is a mutation in the underlying DNA, the resulting protein machines will often be better.

In cancer, a subset of genes usually change, and each of these genes can change in hundreds of different ways, Crogan said. In addition, the function of a particular protein may be different in different cell types, so a mutation in a breast cancer cell may have a different effect on the protein complex than the same mutation in the throat cell.

The goal of CCMI was to map a star map of a protein complex made up of about 60 proteins that are commonly associated with breast cancer or head and neck cancer and see what each healthy cell looks like. In addition to that effort, they mapped out how protein complexes are affected by hundreds of different gene mutations in two cancer cell lines.

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Currently, doctors look for a small number of mutated genes as biomarkers to decide whether or not to prescribe a specific prescription. For example, patients with breast cancer who have the HER2 gene mutation are given Herceptin given because it is designed to work best for them.

“The problem is that there are still a few genes that work this way, providing reliable biomarkers that clearly work with FDA-approved drugs.” “Our studies provide a new definition of biomarkers based on large, multi-protein complexes, not based on a single gene or protein.”

Since each protein complex includes mutations from a larger collection of genes, it is generally relevant for more patients, Ideker said.

For example, XRCC5 is a DNA-repair gene that converts only 2 percent to colon cancer, limiting the usefulness of this biomarker. Now, however, researchers can look at the new map of CCMI’s cancer protein complex and see that XRCC5 is part of a modified 15-protein assembly in 14 percent of patients and that these patients are generally very resistant to standard therapy.

“Indeed, by targeting multiple components of this ‘oncogenic network’, our collaborative studies will pave the way for the development of more effective combination cancer therapies, while preventing treatment,” said co-author J. Silvio Gutkind.
Associate Director of the Department of Pharmacology and Basic Sciences at the UCSD School of Medicine and Co-Director of the Head and Neck Cancer Center at Moores Cancer Center. “These studies of breast and oral cancer can now be extended to the detriment of most people.”

The most powerful aspect of these broad protein interaction maps is that they can shed the same light on many other conditions, Crogan said. For example, the team is also working on similar studies of protein interactions in mental and neurodegenerative disorders and infectious diseases.

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This News Originally From – The Epoch Times

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