DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism

Venkatrao Vantaku, Chandra Sekhar Amara, Danthasinghe Waduge Badrajee Piyarathna, Sri Ramya Donepudi, Chandrashekar R. Ambati, Vasanta Putluri, Wei Tang, Kimal Rajapakshe, Marcos Roberto Estecio, Martha K. Terris, Patricia D. Castro, Michael M. Ittmann, Stephen B. Williams, Seth P. Lerner, Arun Sreekumar, Roni Bollag, Cristian Coarfa, Michael D. Kornberg, Yair Lotan, Stefan AmbsNagireddy Putluri

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Pages (from-to)1332-1340
    Number of pages9
    JournalCarcinogenesis
    Volume40
    Issue number11
    DOIs
    StatePublished - Nov 25 2019

    Fingerprint

    Xenobiotics
    DNA Methylation
    Urinary Bladder Neoplasms
    African Americans
    CpG Islands
    Methylation
    S-Adenosylhomocysteine
    S-Adenosylmethionine
    Glucuronic Acid
    Metabolomics
    Survival
    Enzymes
    Metabolic Networks and Pathways
    Genetic Promoter Regions
    Epigenomics
    Liquid Chromatography
    Mass Spectrometry
    Neoplasms
    Glucose
    Messenger RNA

    ASJC Scopus subject areas

    • Cancer Research

    Cite this

    Vantaku, V., Amara, C. S., Piyarathna, D. W. B., Donepudi, S. R., Ambati, C. R., Putluri, V., ... Putluri, N. (2019). DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism. Carcinogenesis, 40(11), 1332-1340. https://doi.org/10.1093/carcin/bgz128

    DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism. / Vantaku, Venkatrao; Amara, Chandra Sekhar; Piyarathna, Danthasinghe Waduge Badrajee; Donepudi, Sri Ramya; Ambati, Chandrashekar R.; Putluri, Vasanta; Tang, Wei; Rajapakshe, Kimal; Estecio, Marcos Roberto; Terris, Martha K.; Castro, Patricia D.; Ittmann, Michael M.; Williams, Stephen B.; Lerner, Seth P.; Sreekumar, Arun; Bollag, Roni; Coarfa, Cristian; Kornberg, Michael D.; Lotan, Yair; Ambs, Stefan; Putluri, Nagireddy.

    In: Carcinogenesis, Vol. 40, No. 11, 25.11.2019, p. 1332-1340.

    Research output: Contribution to journalArticle

    Vantaku, V, Amara, CS, Piyarathna, DWB, Donepudi, SR, Ambati, CR, Putluri, V, Tang, W, Rajapakshe, K, Estecio, MR, Terris, MK, Castro, PD, Ittmann, MM, Williams, SB, Lerner, SP, Sreekumar, A, Bollag, R, Coarfa, C, Kornberg, MD, Lotan, Y, Ambs, S & Putluri, N 2019, 'DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism', Carcinogenesis, vol. 40, no. 11, pp. 1332-1340. https://doi.org/10.1093/carcin/bgz128
    Vantaku, Venkatrao ; Amara, Chandra Sekhar ; Piyarathna, Danthasinghe Waduge Badrajee ; Donepudi, Sri Ramya ; Ambati, Chandrashekar R. ; Putluri, Vasanta ; Tang, Wei ; Rajapakshe, Kimal ; Estecio, Marcos Roberto ; Terris, Martha K. ; Castro, Patricia D. ; Ittmann, Michael M. ; Williams, Stephen B. ; Lerner, Seth P. ; Sreekumar, Arun ; Bollag, Roni ; Coarfa, Cristian ; Kornberg, Michael D. ; Lotan, Yair ; Ambs, Stefan ; Putluri, Nagireddy. / DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism. In: Carcinogenesis. 2019 ; Vol. 40, No. 11. pp. 1332-1340.
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    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.",
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    AU - Amara, Chandra Sekhar

    AU - Piyarathna, Danthasinghe Waduge Badrajee

    AU - Donepudi, Sri Ramya

    AU - Ambati, Chandrashekar R.

    AU - Putluri, Vasanta

    AU - Tang, Wei

    AU - Rajapakshe, Kimal

    AU - Estecio, Marcos Roberto

    AU - Terris, Martha K.

    AU - Castro, Patricia D.

    AU - Ittmann, Michael M.

    AU - Williams, Stephen B.

    AU - Lerner, Seth P.

    AU - Sreekumar, Arun

    AU - Bollag, Roni

    AU - Coarfa, Cristian

    AU - Kornberg, Michael D.

    AU - Lotan, Yair

    AU - Ambs, Stefan

    AU - Putluri, Nagireddy

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    N2 - 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.

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