Histone Modifications Used as Predictive Biomarkers in Pancreatic Cancer

Histone modifications can be used to predict prognosis and response to treatment in subsets of patients with pancreatic cancer, according to researchers at UCLA’s Jonsson Comprehensive Cancer Center. Their study appears in the Journal of Clinical Oncology in a paper titled “Cellular Histone Modification Patterns Predict Prognosis and Treatment Response in Resectable Pancreatic Adenocarcinoma: Results From RTOG 9704.”

Jonsson Cancer Center researchers, led by Siavash Kurdistani, M.D., and David Seligson, M.D., developed and patented an immunohistochemistry assay to measure levels of specific histone modifications within cells. They previously showed that low cellular levels of particular histones could determine which prostate cancer patients were more likely to suffer a recurrence and which patients with lung and kidney cancers would experience poorer survival rates.

In the current study, the scientists used tissues from a 195-patient cohort enrolled in the radiation therapy oncology group (RTOG) 9704 trial, a multicenter, Phase III study of pancreatic cancer comparing adjuvant Gemcitabine with 5-FU, and a separate 140-patient cohort of patients with stage 1 or 2 pancreatic cancer from UCLA. Immunohistochemistry was performed for histone H3 lysine 4 dimethylation (H3K4me2), histone H3 lysine 9 dimethylation (H3K9me2), and histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures.

Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival, the investigators report. Combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival in the UCLA cohort. In subgroup analyses, histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil but not gemcitabine in RTOG 9704.

“Cellular levels of histone modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions including the use of fluorouracil chemotherapy,” the authors conclude.

Next, Dr. Kurdistani and David Dawson, M.D., Ph.D., senior author of this study, will be pursuing research in cell lines and animal models to determine what, if any, role the histone modifications have in causing the development of aggressive forms of pancreatic cancer.

“If you can uncover the mechanism of how the histone modifications are associated with cancer development and/or progression, you may be able to design strategies to interfere with that process,” Dr. Kurdistani notes.  “Such a strategy could be the basis for a targeted therapy or chemoprevention approach.”