Justin Hwang FOXA1 mutations in prostate cancer

New research from MCC reveals the two faces of FOXA1 mutations in prostate cancer

An exciting new study led by Dr. Justin Hwang, a researcher at the Masonic Cancer Center (MCC), University of Minnesota, and assistant professor in the U of M Medical School, has shed light on the role of FOXA1 mutations in prostate cancer. The research was published in Clinical Cancer Research in early January 2025. These FOXA1 mutations occur in about 15 percent of prostate cancer patients, and were discovered to fall into seven distinct subclasses—each with unique effects on patient outcomes and tumor characteristics.

“Our study demonstrates that not all mutations in genes that regulate cancer progression, such as FOXA1, are created equal,” explains Dr. Hwang. “Some lead to vastly different outcomes in prostate cancer patients and even disproportionately affect patients of different races. By diving deep into protein structure, genomic data, and clinical outcomes, we were able to classify FOXA1 mutations in a way that could really help doctors make better decisions for their patients in the future. It’s a reminder that we need to understand these mutations thoroughly before jumping to conclusions about prognosis or treatment.”

Using genetic sequencing data from nearly 5,000 patients provided by Caris Life Sciences, Hwang and his study team—which includes Dr. Emmanuel Antonarakis, MCC’s associate director of translational research and U of M Medical School Clarke Endowed professor—uncovered how different types of FOXA1 mutations, such as missense mutations, truncations, and amplifications, affect the tumor’s biology and immune response. These mutations occur in specific protein domains, and knowing which subclass a mutation belongs to can make a big difference when deciding on treatments.

“In prostate cancer, FOXA1 appears to be a two-faced gene”, says Antonarakis. “Some mutations increase the cancer’s addiction to androgens making them more sensitive to hormonal therapies, while other FOXA1 mutations cause the prostate cancer to shift to a hormone-independent version that requires chemotherapy”.

The study team is calling on diagnostic testing companies to include FOXA1 subclasses in their reports, especially for prostate cancer patients. Hwang stressed that these insights could lead to more personalized treatment strategies tailored to the unique mutations present in each patient’s cancer. 

“Ultimately, by helping doctors and researchers better understand FOXA1 mutations,” Hwang adds, “our study offers hope for more precise and effective prostate cancer treatments in the future.”

Looking ahead, the research team will study FOXA1 mutations in a larger, more diverse group of patients across the Midwest. At the same time, researchers at the University of Minnesota are developing advanced cell models using next-generation DNA-editing technology—a special technology being developed to treat genetic diseases—to better understand how these mutations work at a molecular level.

This work was made possible through funding from MCC’s 2022 Cancer Research Translational Initiative (CRTI) Translational Working Group pilot award and NIH/NCI R37.