Grant Number:	5R01CA158286-02 Interpret this number
Primary Investigator:	Rozek, Laura
Organization:	University Of Michigan At Ann Arbor
Project Title:	Integrative Epigenomic/Genomic Profiling and Biomarker Discovery in Hpv+ and HPV
Fiscal Year:	2012

DESCRIPTION (provided by applicant): It is clear that differences exist between the molecular mechanisms in HPV-induced squamous cell carcinomas (SCCs) and those linked to tobacco carcinogens. Currently, treatment of head and neck SCC (HNSCC) is not based on HPV status. The incidence of tonsil and tongue cancers have been increasing annually and many contain high risk HPV. It is important to understand differing factors of carcinogenesis in HPV(+) and HPV(-) HNSCC to develop personalized treatment approaches. To do this requires more knowledge of the molecular mechanisms that drive tumor behavior and response to therapy in HPV(+) vs HPV(-) SCCs. Our preliminary data indicate that there are striking epigenetic differences between HPV+ and HPV- tumors, but to appreciate these differences, they must be considered in light of gene expression and other somatic changes. We propose to use gene expression, DNA methylation and histone modifications, and copy number changes to identify molecular mechanisms that define and differentiate HPV-induced from carcinogen-induced HNSCC. The overall objective of this proposal is to understand the differences in the aberrant molecular pathways leading to carcinogenesis in HPV(+) and HPV(-) HNSCCs taking into account smoking and additional epidemiological factors. Our central hypothesis is that by using advanced, integrative bioinformatics methods on the genomic and epigenomic profiles of HPV+ and HPV- tumor cells, we will be able to subdivide HPV+ and HPV- tumors into high and low risk subsets. Our long term goal is to accurately predict and apply the most appropriate treatment regimes for individual HPV+ and HPV- HNSCCs based on smoking, molecular factors and new targets identified in this study. In the first aim, whole-genome analyses will be performed on a well-characterized panel of HPV+ and HPV- oropharyngeal cell lines and primary oral/oropharyngeal (OPSCC) tumors from HPV+ smokers, HPV+ non-smokers, and HPV- ever smokers, and relevant normal cells to define and distinguish aberrant molecular pathways for each etiology. Aim 2 will integrate and characterize genomic, epigenomic and corresponding gene expression changes to prioritize results based on clinical relevancy by developing, validating, and applying integrative methods for the analysis of multifaceted deep sequencing data. Aim 3 will identify and validate top prioritized findings in a larger sample of primary tumor samples. This will confirm clinically important biomarkers and identify aberrant changes associated with etiology, recurrence, or survival in tumor cells from clinical specimens. Our tiered approach from high-throughput technologies to validation in a patient population together with innovative bioinformatics approaches will pave the way to understanding and exploiting somatic differences for optimal therapeutic application. Collectively, our proposed studies will bring us closer to personalized treatment regimes for OPSCCs, as well as provide valuable, accessible tools to the research community for integrative analysis and interpretation of deep sequencing data.




Whole-genome CpG-resolution DNA Methylation Profiling of HNSCC Reveals Distinct Mechanisms of Carcinogenesis for Fine-scale HPV+ Cancer Subtypes.
Authors: Qin T. , Li S. , Henry L.E. , Chou E. , Cavalcante R.G. , Garb B.F. , D'Silva N.J. , Rozek L.S. , Sartor M.A. .
Source: Cancer Research Communications, 2023 Aug; 3(8), p. 1701-1715.
EPub date: 2023-08-30 00:00:00.0.
PMID: 37654626
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5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers.
Authors: Liu S. , de Medeiros M.C. , Fernandez E.M. , Zarins K.R. , Cavalcante R.G. , Qin T. , Wolf G.T. , Figueroa M.E. , D'Silva N.J. , Rozek L.S. , et al. .
Source: Clinical Epigenetics, 2020-11-17 00:00:00.0; 12(1), p. 175.
EPub date: 2020-11-17 00:00:00.0.
PMID: 33203436
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The role of the histone H3 variant CENPA in prostate cancer.
Authors: Saha A.K. , Contreras-Galindo R. , Niknafs Y.S. , Iyer M. , Qin T. , Padmanabhan K. , Siddiqui J. , Palande M. , Wang C. , Qian B. , et al. .
Source: The Journal Of Biological Chemistry, 2020-06-19 00:00:00.0; 295(25), p. 8537-8549.
EPub date: 2020-05-05 00:00:00.0.
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Significant association between host transcriptome-derived HPV oncogene E6* influence score and carcinogenic pathways, tumor size, and survival in head and neck cancer.
Authors: Qin T. , Koneva L.A. , Liu Y. , Zhang Y. , Arthur A.E. , Zarins K.R. , Carey T.E. , Chepeha D. , Wolf G.T. , Rozek L.S. , et al. .
Source: Head & Neck, 2020-05-14 00:00:00.0; , .
EPub date: 2020-05-14 00:00:00.0.
PMID: 32406560
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Poly-Enrich: count-based methods for gene set enrichment testing with genomic regions.
Authors: Lee C.T. , Cavalcante R.G. , Lee C. , Qin T. , Patil S. , Wang S. , Tsai Z.T.Y. , Boyle A.P. , Sartor M.A. .
Source: Nar Genomics And Bioinformatics, 2020 Mar; 2(1), p. lqaa006.
EPub date: 2020-02-06 00:00:00.0.
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IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response.
Authors: Núñez F.J. , Mendez F.M. , Kadiyala P. , Alghamri M.S. , Savelieff M.G. , Garcia-Fabiani M.B. , Haase S. , Koschmann C. , Calinescu A.A. , Kamran N. , et al. .
Source: Science Translational Medicine, 2019-02-13 00:00:00.0; 11(479), .
PMID: 30760578
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Expressed HNSCC variants by HPV-status in a well-characterized Michigan cohort.
Authors: Qin T. , Zhang Y. , Zarins K.R. , Jones T.R. , Virani S. , Peterson L.A. , McHugh J.B. , Chepeha D. , Wolf G.T. , Rozek L.S. , et al. .
Source: Scientific Reports, 2018-07-30 00:00:00.0; 8(1), p. 11458.
EPub date: 2018-07-30 00:00:00.0.
PMID: 30061624
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Integrating DNA Methylation and Hydroxymethylation Data with the Mint Pipeline.
Authors: Cavalcante R.G. , Patil S. , Park Y. , Rozek L.S. , Sartor M.A. .
Source: Cancer Research, 2017-11-01 00:00:00.0; 77(21), p. e27-e30.
PMID: 29092933
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HPV Integration in HNSCC Correlates with Survival Outcomes, Immune Response Signatures, and Candidate Drivers.
Authors: Koneva L.A. , Zhang Y. , Virani S. , Hall P.B. , McHugh J.B. , Chepeha D.B. , Wolf G. , Carey T.E. , Rozek L.S. , Sartor M.A. .
Source: Molecular Cancer Research : Mcr, 2017-09-19 00:00:00.0; , .
EPub date: 2017-09-19 00:00:00.0.
PMID: 28928286
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annotatr: genomic regions in context.
Authors: Cavalcante R.G. , Sartor M.A. .
Source: Bioinformatics (oxford, England), 2017-08-01 00:00:00.0; 33(15), p. 2381-2383.
PMID: 28369316
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Cigarette use, comorbidities, and prognosis in a prospective head and neck squamous cell carcinoma population.
Authors: Peterson L.A. , Bellile E.L. , Wolf G.T. , Virani S. , Shuman A.G. , Taylor J.M. , Rozek L.S. , University of Michigan Head and Neck Specialized Program of Research Excellence Program .
Source: Head & Neck, 2016 Dec; 38(12), p. 1810-1820.
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Subtypes of HPV-Positive Head and Neck Cancers Are Associated with HPV Characteristics, Copy Number Alterations, PIK3CA Mutation, and Pathway Signatures.
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Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2016-09-15 00:00:00.0; 22(18), p. 4735-45.
EPub date: 2016-09-15 00:00:00.0.
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Stability of methylation markers in head and neck squamous cell carcinoma.
Authors: Virani S. , Light E. , Peterson L.A. , Sartor M.A. , Taylor J.M. , McHugh J.B. , Wolf G.T. , Rozek L.S. , Investigators of the University of Michigan Head and Neck Specialized Programs of Research Excellence (SPORE) Program .
Source: Head & Neck, 2016 Apr; 38 Suppl 1, p. E1325-31.
PMID: 26566081
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RNA-Enrich: a cut-off free functional enrichment testing method for RNA-seq with improved detection power.
Authors: Lee C. , Patil S. , Sartor M.A. .
Source: Bioinformatics (oxford, England), 2016-04-01 00:00:00.0; 32(7), p. 1100-2.
EPub date: 2015-11-25 00:00:00.0.
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NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas.
Authors: Virani S. , Bellile E. , Bradford C.R. , Carey T.E. , Chepeha D.B. , Colacino J.A. , Helman J.I. , McHugh J.B. , Peterson L.A. , Sartor M.A. , et al. .
Source: Bmc Cancer, 2015-10-30 00:00:00.0; 15, p. 825.
EPub date: 2015-10-30 00:00:00.0.
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Epigenetic alterations in metastatic cutaneous carcinoma.
Authors: Darr O.A. , Colacino J.A. , Tang A.L. , McHugh J.B. , Bellile E.L. , Bradford C.R. , Prince M.P. , Chepeha D.B. , Rozek L.S. , Moyer J.S. .
Source: Head & Neck, 2015 Jul; 37(7), p. 994-1001.
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PePr: a peak-calling prioritization pipeline to identify consistent or differential peaks from replicated ChIP-Seq data.
Authors: Zhang Y. , Lin Y.H. , Johnson T.D. , Rozek L.S. , Sartor M.A. .
Source: Bioinformatics (oxford, England), 2014-09-15 00:00:00.0; 30(18), p. 2568-75.
EPub date: 2014-09-15 00:00:00.0.
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MethylSig: a whole genome DNA methylation analysis pipeline.
Authors: Park Y. , Figueroa M.E. , Rozek L.S. , Sartor M.A. .
Source: Bioinformatics (oxford, England), 2014-09-01 00:00:00.0; 30(17), p. 2414-22.
EPub date: 2014-09-01 00:00:00.0.
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Broad-Enrich: functional interpretation of large sets of broad genomic regions.
Authors: Cavalcante R.G. , Lee C. , Welch R.P. , Patil S. , Weymouth T. , Scott L.J. , Sartor M.A. .
Source: Bioinformatics (oxford, England), 2014-09-01 00:00:00.0; 30(17), p. i393-400.
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ChIP-Enrich: gene set enrichment testing for ChIP-seq data.
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Source: Nucleic Acids Research, 2014 Jul; 42(13), p. e105.
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The circadian clock in oral health and diseases.
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Epigenetics: relevance and implications for public health.
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Comprehensive analysis of DNA methylation in head and neck squamous cell carcinoma indicates differences by survival and clinicopathologic characteristics.
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LRpath analysis reveals common pathways dysregulated via DNA methylation across cancer types.
Authors: Kim J.H. , Karnovsky A. , Mahavisno V. , Weymouth T. , Pande M. , Dolinoy D.C. , Rozek L.S. , Sartor M.A. .
Source: Bmc Genomics, 2012-10-04 00:00:00.0; 13, p. 526.
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Pretreatment dietary intake is associated with tumor suppressor DNA methylation in head and neck squamous cell carcinomas.
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Cancer epigenetics: a brief review.
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