Grant Number:	5U01CA238592-05 Interpret this number
Primary Investigator:	Burk, Robert
Organization:	Albert Einstein College Of Medicine
Project Title:	Investigations Into the Molecular Pathogenesis of Cervical Glandular Neoplasias
Fiscal Year:	2024

ABSTRACT More than 12,000 women are diagnosed with cervical cancer, an HPV-associated malignancy, annually in the U.S. There are two major histologic forms of cervix cancer: squamous cell carcinoma (SCC) and adenocarcinoma (ADENO). Importantly, SCC can be prevented through cervical cytology screening programs, whereas ADENO cannot. While there is a prophylactic vaccine against HPV, uptake of HPV vaccination in the U.S. has been poor and there are several generations of women who are already exposed to HPV infection and will not be helped by HPV vaccination. Therefore, cervical screening at a cost of over $6 billion per year will be needed for several decades at least. Understanding the molecular pathogenesis of ADENO has important public health value in order to facilitate the prevention of ADENO, for which current screening strategies are inadequate. In the US and Europe, HPV16, 18, and 45 infections account for >95% of AIS/ADENO. We examined viral methylation of HPV16/18/45 AIS (n=27) and cervical intraepithelial neoplasia grade 3 (CIN3) (n=63) cases compared to 90 HPV16/18/45 control infections with 20,000) in whom the vast majority of ADENO occur, to measure host and HPV viral methylation changes and HPV viral integration to molecularly define the natural history of ADENO. We will compare and contrast these findings with the better known natural history of SCC. Ultimately, we will develop a risk-prediction model for AIS/ADENO precursors using HPV genotypes, HPV viral and host gene epigenetics, and HPV viral integration.

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Publications

Somatic mutations in 3929 HPV positive cervical cells associated with infection outcome and HPV type.
Authors: Pinheiro M. , Wentzensen N. , Dean M. , Yeager M. , Chen Z. , Shastry A. , Boland J.F. , Bass S. , Burdett L. , Lorey T. , et al. .
Source: Nature Communications, 2024-09-12 00:00:00.0; 15(1), p. 7895.
EPub date: 2024-09-12 00:00:00.0.
PMID: 39266536
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A novel human papillomavirus and host DNA methylation score and detection of cervical adenocarcinoma.
Authors: Gradissimo A. , Clarke M.A. , Xue X. , Castle P.E. , Raine-Bennett T.R. , Schiffman M. , Wentzensen N. , Strickler H.D. , Burk R.D. .
Source: Journal Of The National Cancer Institute, 2023-12-06 00:00:00.0; 115(12), p. 1535-1543.
PMID: 37467068
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Distinguishing Genetic Drift from Selection in Papillomavirus Evolution.
Authors: Burk R.D. , Mirabello L. , DeSalle R. .
Source: Viruses, 2023-07-26 00:00:00.0; 15(8), .
EPub date: 2023-07-26 00:00:00.0.
PMID: 37631973
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The combined finding of HPV 16, 18, or 45 and cytologic Atypical Glandular Cells (AGC) indicates a greatly elevated risk of in situ and invasive cervical adenocarcinoma.
Authors: Schiffman M. , Mirabello L. , Egemen D. , Befano B. , Xiao Y. , Wentzensen N. , Raine-Bennett T. , Nayar R. , Cheung L.C. , Rositch A. , et al. .
Source: Gynecologic Oncology, 2023 Jul; 174, p. 253-261.
EPub date: 2023-05-25 00:00:00.0.
PMID: 37243996
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HPV16 E7 Nucleotide Variants Found in Cancer-Free Subjects Affect E7 Protein Expression and Transformation.
Authors: Lou H. , Boland J.F. , Li H. , Burk R. , Yeager M. , Anderson S.K. , Wentzensen N. , Schiffman M. , Mirabello L. , Dean M. .
Source: Cancers, 2022-10-06 00:00:00.0; 14(19), .
EPub date: 2022-10-06 00:00:00.0.
PMID: 36230818
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Redesign of a rapid, low-cost HPV typing assay to support risk-based cervical screening and management.
Authors: Desai K.T. , Adepiti C.A. , Schiffman M. , Egemen D. , Gage J.C. , Wentzensen N. , de Sanjose S. , Burk R.D. , Ajenifuja K.O. .
Source: International Journal Of Cancer, 2022-10-01 00:00:00.0; 151(7), p. 1142-1149.
EPub date: 2022-06-24 00:00:00.0.
PMID: 35666530
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molBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history.
Authors: Usyk M. , Schlecht N.F. , Pickering S. , Williams L. , Sollecito C.C. , Gradissimo A. , Porras C. , Safaeian M. , Pinto L. , Herrero R. , et al. .
Source: Nature Communications, 2022-01-11 00:00:00.0; 13(1), p. 233.
EPub date: 2022-01-11 00:00:00.0.
PMID: 35017496
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Phylogenomic Analysis of Human Papillomavirus Type 31 and Cervical Carcinogenesis: A Study of 2093 Viral Genomes.
Authors: Pinheiro M. , Harari A. , Schiffman M. , Clifford G.M. , Chen Z. , Yeager M. , Cullen M. , Boland J.F. , Raine-Bennett T. , Steinberg M. , et al. .
Source: Viruses, 2021-09-28 00:00:00.0; 13(10), .
EPub date: 2021-09-28 00:00:00.0.
PMID: 34696378
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K-Mer Analyses Reveal Different Evolutionary Histories of Alpha, Beta, and Gamma Papillomaviruses.
Authors: Chen Z. , Utro F. , Platt D. , DeSalle R. , Parida L. , Chan P.K.S. , Burk R.D. .
Source: International Journal Of Molecular Sciences, 2021-09-06 00:00:00.0; 22(17), .
EPub date: 2021-09-06 00:00:00.0.
PMID: 34502564
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A study of type-specific HPV natural history and implications for contemporary cervical cancer screening programs.
Authors: Demarco M. , Hyun N. , Carter-Pokras O. , Raine-Bennett T.R. , Cheung L. , Chen X. , Hammer A. , Campos N. , Kinney W. , Gage J.C. , et al. .
Source: Eclinicalmedicine, 2020 May; 22, p. 100293.
EPub date: 2020-04-25 00:00:00.0.
PMID: 32510043
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