Molecular study defines the contributions of key genes, proteins to endometrial cancer

The most comprehensive molecular study of endometrial cancer to date has further defined the contributions of key genes and proteins to the disease, say its authors.

Published online February 13 in Cell, the study suggests new treatment approaches that could be tailored for each patient, as well as potential biological targets for future drug design.

Led by researchers from NYU Grossman School of Medicine and more than a dozen other institutions, the team reached its conclusions by measuring levels of key proteins, the workhorse molecules that make up cellular structures and signaling networks.

Controlled by instructions encoded in genes, protein levels in cancer cells are the functional result of genetic changes that affect risk for endometrial cancer, researchers say. Focused on proteomics, the large-scale analyses of protein functions and interactions, the study compared protein levels in 95 uterine tumors and 49 normal uterine tissue samples.

While more time-consuming and expensive, proteomics reveals insights into cancer risk that cannot be found by experiments that look at changes in the genetic code alone.

Proteomics identifies the proteins that are most active in a specific tumor, which potentially enables the design of treatments that will work best against that tumor in particular."

David Fenyö, PhD, study senior co-author, professor in the Department of Biochemistry and Molecular Pharmacology and faculty in the Institute for Systems Genetics at NYU Langone Health

Endometrial cancer, which arises in the lining of the uterus, is the sixth most common cancer in women globally and resulted in 12,160 deaths in the United States in 2019. While most women diagnosed in the early stages can be cured, some endometrial tumors can recur, which comes typically with far worse clinical outcomes.

The new work builds on The Cancer Genome Atlas, or TCGA, a landmark research effort that first outlined the genetic underpinnings of many cancers in 2013. Like TCGA, the new study sought to look not at any single aspect of molecular biology; instead, it investigated all players involved in a given set of cancer cells, from the molecular "letters" making up DNA, to the RNA genetic material that DNA is converted into, to the proteins built based on the RNA.

The study also examined the chemical changes to proteins, called post-translational modifications, which determine when and where the proteins are "switched on or off". Altogether, the researchers took more than 12 million measurements of differences between normal and cancerous cells in DNA and RNA, protein levels, and in chemical changes to DNA and proteins.

The NYU Langone research team played a major role in a key finding of the study, which revealed a new way to tell apart a highly aggressive type of endometrial cancer from a less aggressive type that looks similar under a microscope. Telling the two types apart would help clinicians to better fit treatment approaches to a given patient, and to do so earlier in the course of the disease, say the authors.

One subtype of endometrial cancer, the endometrioid subtype, is often identified early, and comprises about 85 percent of all endometrial cancers. A second subtype, the serous subtype, is more aggressive, is typically identified later, and accounts for more deaths than endometrioid tumors. To complicate matters, there is within the endometrioid group an aggressive subset of tumors with molecular markers that are more similar to the serous subtype.

The NYU Langone team focused much of their work on determining what distinguishes these aggressive endometrioid tumors from the serous tumors and the less aggressive endometrioid tumors. They found a subset of proteins that were phosphorylated - had a certain post-translational modification that switches on proteins - in the aggressive subset of endometrioid tumors and in serous tumors, but not in the less aggressive subset of endometrioid tumors. Moreover, the researchers found that some of these hyperactive proteins can be targeted by drugs that are currently approved by the U.S. Food and Drug Administration for other purposes.

In addition, the field had previously established that some people with the less aggressive subset of endometrioid tumors have a genetic difference (mutation) that overproduces the protein beta-catenin, which results in a poor prognosis.

The NYU Langone team found evidence that the high levels of beta-catenin in these seemingly less aggressive tumors are linked to an increased activity of a signaling pathway called Wnt, which is known to spur abnormal cell growth.

"For many years scientists have been using genomics, the study of the genetic code, which is a very effective way but a relatively basic way to look at cancer," says study co-lead author Emily Kawaler, a student at NYU Grossman School of Medicine. "But if we add on all of these extra levels--proteins, RNA, and the ways proteins talk to each other--then we can learn even more about how cancer is actually working."

Source:
Journal reference:

Dou, Y., et al. (2020) Proteogenomic Characterization of Endometrial Carcinoma. Cell. doi.org/10.1016/j.cell.2020.01.026.

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