DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism
Abstract
Racial/ethnic disparities have a significant impact on bladder cancer outcomes with African American patients demonstrating inferior survival over European-American patients. We hypothesized that epigenetic difference in methylation of tumor DNA is an underlying cause of this survival health disparity. We analyzed bladder tumors from African American and European-American patients using reduced representation bisulfite sequencing (RRBS) to annotate differentially methylated DNA regions. Liquid chromatography–mass spectrometry (LC-MS/MS) based metabolomics and flux studies were performed to examine metabolic pathways that showed significant association to the discovered DNA methylation patterns. RRBS analysis showed frequent hypermethylated CpG islands in African American patients. Further analysis showed that these hypermethylated CpG islands in patients are commonly located in the promoter regions of xenobiotic enzymes that are involved in bladder cancer progression. On follow-up, LC-MS/MS revealed accumulation of glucuronic acid, S-adenosylhomocysteine, and a decrease in S-adenosylmethionine, corroborating findings from the RRBS and mRNA expression analysis indicating increased glucuronidation and methylation capacities in African American patients. Flux analysis experiments with 13C-labeled glucose in cultured African American bladder cancer cells confirmed these findings. Collectively, our studies revealed robust differences in methylation-related metabolism and expression of enzymes regulating xenobiotic metabolism in African American patients indicate that race/ethnic differences in tumor biology may exist in bladder cancer.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 08, 2019
- Source ID
- 10.1093/carcin/bgz128
Entities
People
- Arun Sreekumar
- Chandra Sekhar Amara
- Chandrashekar R. Ambati
- Cristian Coarfa
- Danthasinghe Waduge Badrajee Piyarathna
- Kimal Rajapakshe
- Marcos Roberto Estecio
- Martha K. Terris
- Michael D Kornberg
- Michael E. Debakey
- Michael M. Ittmann
- Nagireddy Putluri
- Patricia D Castro
- Roni Bollag
- Seth P. Lerner
- Sri Ramya Donepudi
- Stefan Ambs
- Stephen B Williams
- Vasanta Putluri
- Venkatrao Vantaku
- Wei Tang
- Yair Lotan
Organizations
- American Cancer Society
- Augusta University
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- Dan L. Duncan Cancer Center, Baylor College of Medicine
- Johns Hopkins University
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of Texas Medical Branch
- University of Texas Southwestern Medical Center
- University of Texas at Austin