An unexplored transcription factor, ZNF92, that is distinctively over-expressed in breast cancer has been found to be associated with prognosis and cell-of-origin, according to a study by Weill Cornell Medicine investigators.
A gene-centric view of cancer has been the dominant narrative in cancer research. Over the years, genes have been the main focus in understanding how tumors behave and respond to treatment. However, new research published in NJP Breast Cancer reveals the importance of the cell context of a mutation. Tumors can arise in different organs and may have differences because of their tissue origin. When researchers zoom in on a single organ, they can determine the tumor’s particular cell type origin. “This is the first time we are able to show that a breast cell-of-origin signature predicts outcome in actual breast cancer patients,” stated Dr. Tan Ince, professor of pathology and laboratory medicine.
Investigators identified a cell-of-origin associated prognostic gene expression signature, ET-9, that correlates with a shorter breast cancer survival rate. “If you examine patients who have alterations in this cell-of-origin signature, they have a six to nine years shorter survival time compared to patients who don’t have alterations,” said Dr. Ince. “We realized that about one-third of this signature was associated with a transcription factor, ZNF92.” Transcription factors are proteins that regulate the rate of transcription of genes from DNA into RNA, or how genes are expressed. ZNF92, which was identified in 1900s, has not been explored in any previous papers relating to cancer, was found to be almost exclusively over-expressed in breast cancer. Working in uncharted territory, investigators found the 29 genes in the cell-of-origin signature associated with ZNF92 demonstrated poor outcomes in all breast cancer subtypes. It's important to note that this research is also different from other studies that have discovered prognostic signatures. Instead of conducting an omics study, which has been the leading method, investigators took a hypothesis-based approach. “We think that there’s quite a bit of discovery left to be made with that approach,” said Dr. Ince.
Looking ahead, Dr. Ince and his colleagues hope to further study the cell-of-origin signature and ZNF92 in human breast cancers to translate their work into a biomarker. His team is also working to find a drug combination that targets the cell-of-origin signature. “Gene mutations are thought to be drivers of cancer,” he said. “The cell-of-origin signature we found may be even more powerful in predicting patient outcome than mutations.”