E2F4 Predictive of Progression and Immunotherapy Efficacy in Bladder Cancer

The biomarker E2F4 predicts survival in breast cancer, and an article recently published in the journal Molecular Cancer Research indicates that E2F4 may also predict progression and immunotherapy efficacy in bladder cancer.

Chao Cheng, PhD

The biomarker E2F4 predicts survival in breast cancer, and an article recently published in the journalMolecular Cancer Researchindicates that E2F4 may also predict progression and immunotherapy efficacy in bladder cancer.1This is the first definitive finding after several other biomarkers proposed over the years have not shown reduced or predictive power in independent subsets.

Although transurethral resection is a standard treatment for nonmuscle-invasive bladder cancer (NMIBC), up to 70% of patients develop local recurrences following this treatment. Intravesical BCG (Bacillus Calmett-Guerin) immunotherapy has proven effective in treating the tumors2; however, up to 40% of patients treated with BCG still develop recurrent bladder tumors.1So far, there has been no way of determining who would fall into this category. The E2F4 biomarker could be the answer, according to the authors of the research article, who have been working on the development of E2F4 signature as a biomarker for cancer prognosis since 2013.

“The E2F4 signature was identified from a computational analysis for identifying breast cancer-associated transcriptional regulatory programs,” lead author Chao Cheng, PhD, assistant professor, Dartmouth College, explained in an interview withTargeted Oncology. “Later, we found the signature is also effective in predicting the clinical outcomes of bladder cancer. Since the E2F4 signature reflects the proliferation of tumor cells, which is clinically related in diverse solid tumors, we anticipate that it might also be useful in other solid tumor types, such as prostate cancer.”

The researchers collected data (897 bladder tissue samples) of five bladder gene expression data sets from the Gene Expression Omnibus (GEO) database. They investigated the molecular signature in a single-bladder cancer dataset and confirmed the effectiveness in two meta-bladder datasets consisting of specimens from multiple independent studies. Patients whose tumor had an E2F4 score of more than zero had significantly shorter survival times than those whose score was less than zero, in both nonmuscle-invasive and muscle-invasive bladder cancer.

“It is interesting to observe that the E2F4 signature is predictive to response of nonmuscle [-invasive] bladder cancer to intravesical BCG immunotherapy,” Cheng said. BCG therapy has been used to suppress the progression of bladder cancer for about 40 years, but according to this study, only those patients with high E2F4 activity can significantly benefit from BCG treatment, and those with low E2F4 activity tended to have low progression rate even not being treated by BCG.

“The E2F4 signature is defined based on an integrative analysis that combines cancer gene expression data and ChIP-seq data, which determine genome-wide binding sites of transcription factors,” Cheng explained. “A large number of genomic data (such as ChIP-seq) have been generated in recent years due to the advance of next-generation technologies. These data would provide a useful resource for better understanding cancer mechanism and improving cancer prognosis.”

More detailed research regarding the utility and validity of E2F4 as a bladder cancer biomarker is planned. “We will further validate the prognostic value of the E2F4 signature in bladder cancer in more datasets,” Cheng said. “We will develop a practical and affordable genomic test to implement this signature for clinical applications, and we will also investigate the effectiveness of this signature in other cancer types.”


1. Cheng C, Varn FS, Marsit CJ. E2F4 program is predictive of progression and intravesical immunotherapy efficacy in bladder cancer.Molecular Cancer Research.2015;1(6). doi: 10.1158/1541-7786.MCR-15-0120

2. Anastasiadis A, de Reijke TM. Best practice in the treatment of nonmuscle invasive bladder cancer.Therapeutic Advances in Urology. 2012;4(1):13-32. doi:10.1177/1756287211431976.