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Grant Details

Grant Number: 5R01CA216265-04 Interpret this number
Primary Investigator: Christensen, Brock
Organization: Dartmouth College
Project Title: (PQ3) Immune Epigenetic Biomarkers of Bladder Cancer Outcomes
Fiscal Year: 2020


Abstract

ABSTRACT There are an estimated 765,000 people with a diagnosis of bladder cancer living in the United States and risk of disease recurrence and progression can be high. Frequent, invasive transurethral screening procedures to monitor for recurrence and progression burden both patients and the health care system. A better understanding of the tumor-associated immune responses in bladder cancer patients could provide for more informed clinical decisions on the necessary frequency of invasive follow up procedures and reduce patient morbidity. We propose to leverage an existing population-based study of bladder cancer that includes a range of patient age groups, has several years of follow up, includes patient treatment and outcome data, as well as matched tumor samples. Our collaborative group has developed and extensively validated epigenetic biomarkers of leukocyte subtypes allowing the use of archival DNA to study immune profiles. Here we will use our proven framework to expand our repertoire of leukocyte epigenetic biomarkers to include myeloid derived suppressor cells (MDSC), and test and validate the relation of MDSC and other leukocyte subtypes (including the neutrophil to lymphocyte ratio: NLR), and cell type activation states with bladder cancer outcomes; recurrence, progression, and survival. We will use time-to-event analysis and aim to understand the independent contributions of immune profiles, age at diagnosis, tumor stage and grade, smoking history, and treatment (including BCG immunotherapy), with bladder cancer outcomes. In addition, we propose to measure somatic alteration profiles of bladder tumors from matched subjects and assess the relation of blood immune signatures with tumor methylation and survival to understand the crosstalk between tumor profiles and patient immune responses. Finally, in an exploratory aim we will prospectively investigate both pre-treatment and post- treatment immune signatures in bladder cancer patients. At this opportune time of emerging immunomodulatory therapeutics our existing population-based study resource provides a cost-efficient setting to advance towards improved risk projection in newly diagnosed patients by ushering in a novel and flexible immune monitoring toolkit that can inform clinical decision-making using data on tumor-associated immune responses.



Publications

Enrichment of CpG island shore region hypermethylation in epigenetic breast field cancerization.
Authors: Muse M.E. , Titus A.J. , Salas L.A. , Wilkins O.M. , Mullen C. , Gregory K.J. , Schneider S.S. , Crisi G.M. , Jawale R.M. , Otis C.N. , et al. .
Source: Epigenetics, 2020 Oct; 15(10), p. 1093-1106.
EPub date: 2020-04-07.
PMID: 32255732
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Genome-wide characterization of cytosine-specific 5-hydroxymethylation in normal breast tissue.
Authors: Wilkins O.M. , Johnson K.C. , Houseman E.A. , King J.E. , Marsit C.J. , Christensen B.C. .
Source: Epigenetics, 2020 Apr; 15(4), p. 398-418.
EPub date: 2019-12-16.
PMID: 31842685
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MethylNet: an automated and modular deep learning approach for DNA methylation analysis.
Authors: Levy J.J. , Titus A.J. , Petersen C.L. , Chen Y. , Salas L.A. , Christensen B.C. .
Source: BMC bioinformatics, 2020-03-17; 21(1), p. 108.
EPub date: 2020-03-17.
PMID: 32183722
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Prediagnostic breast milk DNA methylation alterations in women who develop breast cancer.
Authors: Salas L.A. , Lundgren S.N. , Browne E.P. , Punska E.C. , Anderton D.L. , Karagas M.R. , Arcaro K.F. , Christensen B.C. .
Source: Human molecular genetics, 2020-03-13; 29(4), p. 662-673.
PMID: 31943067
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PathFlowAI: A High-Throughput Workflow for Preprocessing, Deep Learning and Interpretation in Digital Pathology.
Authors: Levy J.J. , Salas L.A. , Christensen B.C. , Sriharan A. , Vaickus L.J. .
Source: Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing, 2020; 25, p. 403-414.
PMID: 31797614
Related Citations

PyMethylProcess-convenient high-throughput preprocessing workflow for DNA methylation data.
Authors: Levy J.J. , Titus A.J. , Salas L.A. , Christensen B.C. .
Source: Bioinformatics (Oxford, England), 2019-12-15; 35(24), p. 5379-5381.
PMID: 31368477
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DNA methylation aging clocks: challenges and recommendations.
Authors: Bell C.G. , Lowe R. , Adams P.D. , Baccarelli A.A. , Beck S. , Bell J.T. , Christensen B.C. , Gladyshev V.N. , Heijmans B.T. , Horvath S. , et al. .
Source: Genome biology, 2019-11-25; 20(1), p. 249.
EPub date: 2019-11-25.
PMID: 31767039
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Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data.
Authors: Gervin K. , Salas L.A. , Bakulski K.M. , van Zelm M.C. , Koestler D.C. , Wiencke J.K. , Duijts L. , Moll H.A. , Kelsey K.T. , Kobor M.S. , et al. .
Source: Clinical epigenetics, 2019-08-27; 11(1), p. 125.
EPub date: 2019-08-27.
PMID: 31455416
Related Citations

Absence of an embryonic stem cell DNA methylation signature in human cancer.
Authors: Zhang Z. , Wiencke J.K. , Koestler D.C. , Salas L.A. , Christensen B.C. , Kelsey K.T. .
Source: BMC cancer, 2019-07-19; 19(1), p. 711.
EPub date: 2019-07-19.
PMID: 31324166
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DNA Methylation Changes in Regional Lung Macrophages Are Associated with Metabolic Differences.
Authors: Armstrong D.A. , Chen Y. , Dessaint J.A. , Aridgides D.S. , Channon J.Y. , Mellinger D.L. , Christensen B.C. , Ashare A. .
Source: ImmunoHorizons, 2019-07-02; 3(7), p. 274-281.
EPub date: 2019-07-02.
PMID: 31356157
Related Citations

Molecular and epigenetic profiles of BRCA1-like hormone-receptor-positive breast tumors identified with development and application of a copy-number-based classifier.
Authors: Chen Y. , Wang Y. , Salas L.A. , Miller T.W. , Mark K. , Marotti J.D. , Kettenbach A.N. , Cheng C. , Christensen B.C. .
Source: Breast cancer research : BCR, 2019-01-25; 21(1), p. 14.
EPub date: 2019-01-25.
PMID: 30683142
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MicroRNA-Related Genetic Variants Associated with Survival of Head and Neck Squamous Cell Carcinoma.
Authors: Wilkins O.M. , Titus A.J. , Salas L.A. , Gui J. , Eliot M. , Butler R.A. , Sturgis E.M. , Li G. , Kelsey K.T. , Christensen B.C. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2019 01; 28(1), p. 127-136.
EPub date: 2018-06-07.
PMID: 29880533
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Genome-wide DNA methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis.
Authors: Chen Y. , Armstrong D.A. , Salas L.A. , Hazlett H.F. , Nymon A.B. , Dessaint J.A. , Aridgides D.S. , Mellinger D.L. , Liu X. , Christensen B.C. , et al. .
Source: Clinical epigenetics, 2018-12-10; 10(1), p. 152.
EPub date: 2018-12-10.
PMID: 30526669
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Tracing human stem cell lineage during development using DNA methylation.
Authors: Salas L.A. , Wiencke J.K. , Koestler D.C. , Zhang Z. , Christensen B.C. , Kelsey K.T. .
Source: Genome research, 2018 09; 28(9), p. 1285-1295.
EPub date: 2018-08-02.
PMID: 30072366
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An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray.
Authors: Salas L.A. , Koestler D.C. , Butler R.A. , Hansen H.M. , Wiencke J.K. , Kelsey K.T. , Christensen B.C. .
Source: Genome biology, 2018-05-29; 19(1), p. 64.
EPub date: 2018-05-29.
PMID: 29843789
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