BUFFALO, N.Y.—Roswell Park Comprehensive Cancer Center has identified another promising biomarker for aggressive cancers, this time homing in on the histone H2AX as being potentially significant in aggressive breast cancer. Findings presented at the American Association for Cancer Research meeting in Chicago indicate that breast cancer patients with high levels of H2AX face a worse prognosis than others, but conversely, that those patients may be more responsive to radiation treatment.
Researchers at Roswell Park, led by Dr. Kazuaki Takabe, clinical chief of breast surgery—along with Dr. Eriko Katsuta, a postdoctoral research fellow—initiated their work with a thorough review of the Cancer Genome Atlas, combing through it for a predictive biomarker in breast cancer. After reviewing data from more than 11,000 patients, they found that the presence of high levels of H2AX directly correlated with those patients who saw a worse prognosis. While H2AX is a histone present in all cells, with a known role in DNA repair, a higher H2AX ratio in tumors was present throughout the samples.
“We knew that this histone played a large role in DNA repair, but here we found that H2AX is involved in several different pathways leading to the development of breast cancer,” says Katsuta. “The association between H2AX and a poor outcome was significant for all breast cancer patients, especially those with advanced disease.”
The team also found that tumors with high levels of H2AX were more sensitive to radiation than other tumors. “Our findings suggest that H2AX could be used to identify breast cancer patients who have a poor prognosis but are more likely to respond well to radiation therapy, which could help personalize and improve treatment,” adds Takabe.
The Roswell Park team sees many ways this information can be helpful for earlier detection and better treatment of breast cancer. A localized tumor in the breast itself is often not what causes lethality, but rather when breast cancer metastasizes and travels to other areas in the body where it may be harder to treat.
“When breast cancer settles in the brain, for example,” explains Takabe, “it can locate in a spot that makes surgery difficult or impossible. Likewise, just zapping the area with high doses of radiation may shrink the tumor, but may also lead to radiation-induced dementia. A tumor known to have higher radiosensitivity could possibly eliminate or lessen risky surgeries, while also potentially allowing for lesser amounts of radiation used to target a tumor.”
Takabe emphasizes that computational biology allows for a different approach to research. “Big data and computational biology allow us to do science backwards—we can start with a data-driven commonality, and then dig deeper to find the histone. These tools allow us to identify the possible candidates first, and then undergo molecular testing.”
So far, the data is limited to what the team has gathered through computational analysis, but they are preparing to begin animal testing by the end of 2018. They have the needed cells and will move on to cellular experiments in order to prove the hypothesis suggested by the data. Once the researchers are able to establish their proof of concept, that overexpression of H2AX causes poor prognosis and increased radiosensitivity, they can then move to the next phase of possibly identifying a histone blocker that can minimize such overexpression unless desired for radiation purposes.
With a mission of understanding, preventing and curing cancer, Roswell Park is well known for its work in identifying biomarkers using computational analysis. In 2017, another Roswell team identified an 11-gene signature unique to advanced recurrent prostate cancer that correlates with a more rapid progress to metastasis and decreased overall survival. These findings were followed by an announcement last spring that the prostate cancer team had determined that losing the GPRC6A gene caused prostate cancer cells to become more invasive and metastatic. They also identified specific RNA molecules that normally turn off production of GPRC6A. Their investigation continues now as researchers are working to determine whether GPRC6A and associated microRNAs might predict cancer aggressiveness, thereby identifying aggressive disease early and finding targeted treatments for potentially deadly prostate cancer. Like other Roswell teams, they believe isolating and recognizing these biomarkers will help to identify aggressive and potentially fatal cancers sooner.