CHICAGO, Feb. 13 (Xinhua) — A study of Washington University School of Medicine in St. Louis has revealed the dozens of molecular changes that bring about endometrial cancer, which offers insight into how physicians might be able to better identify which patients will need aggressive treatment and why a common treatment is not effective for some patients.
The study builds on work by The Cancer Genome Atlas (TCGA) which identified the genetic underpinnings of the disease in 2013.
The researchers studied 95 uterine tumors and 49 normal uterine tissue samples. They measured the abundance, modifications and locations of many vital molecular players, including genes, proteins, messenger RNAs, circular RNAs, micro RNAs, and evidence of what they call “post-translational modifications.”
They developed a promising new way to identify tumors that are classified incorrectly as not aggressive but that turn out to be just as invasive as a type of tumor that grows quickly and is more likely than other tumors to kill patients.
One analysis showed how the protein beta-catenin, a well-known actor in many types of cancer, interacts with an important signaling pathway to evade detection and spur cells to grow out of control.
“This is the first delineation of the entire beta-catenin complex in a specific disease,” said Li Ding, a professor of medicine at Washington University School of Medicine in St. Louis. “We know it plays roles in endometrial cancer and colorectal cancer, so this is a major step forward in understanding the details of this important cancer driver.”
The researchers also found that a process that involves packing and unpacking genes happens more often than expected in tumor cells. With more than six feet of DNA squeezed into nearly every human cell, the body must pack it efficiently, but it also needs to unspool the DNA so that other molecular machinery can access it. The researchers found that a key part of the unspooling process, known as histone acetylation, is very active in endometrial cancer.
“Histone acetylation tends to activate genes, which can drive cancer growth,” Ding said. “In theory, we could use information about histone acetylation to predict how aggressive a tumor is likely to be.”
The researchers also discovered that small, often overlooked molecules known as circular RNAs seem to be involved in the transformation that cells undergo when they gain the ability to spread. The process is called the endothelial-to-mesenchymal transition and is what makes endometrial cancer deadly.
The researchers created a new way to determine which patients are most likely to benefit from a treatment known as checkpoint therapy, in which drugs such as pembrolizumab and nivolumab are used to dodge the barriers that some cancer cells use to evade the immune system.
Currently, physicians use a measurement known as “tumor mutation burden” to determine which patients are most likely to benefit from checkpoint therapy in endometrial cancer. Based on the measurements of immune activity in the study, the researchers have proposed a new measure focused on how well a patient’s body flags cancer cells and presents them to the body’s immune system for destruction, a key function for checkpoint inhibitors to be effective.
The study is published Thursday in the journal Cell.