We are now in an era of an FDA approved prophylactic HPV16/18 vaccine for the two major types of HPV causing cervix cancer. Nevertheless, there are many critical questions about the natural history of non-HPV16/18 HPV types associated with cervix cancer and the fine specificity of the vaccine that remain and need to be addressed. The central hypothesis of this application is that DNA mutation and natural selection have driven the evolution of success amongst HPV infections resulting also in the emergence of cancer causing viruses, as a byproduct of filling a specific biological niche. We will utilize epidemiological methods and the analytic tools of evolution and systems biology to study the role of oncogenic HPV types and variants in population-based studies of HPV natural history and cervix neoplasia. We propose 3 specific aims: (1) To define the natural history of the a7 (18-related) and a9 (16-related) HPV types in the HPV Persistence and Progression (PaP) Cohort at Kaiser Permanente Northern California, a new cohort study of 35,000 HR-HPV positive (HC2+) women z 30 yrs of age women and in the 21,000 women from the Portland study with 16 years of follow-up;(2) To determine vaccine efficacy for HPV16/18-variants and related type variants after vaccination with HPV16/18 VLPs in the Costa Rica Vaccine Trial (CVT), a phase III HPV 16/18 vaccine trial of 7500 women 18-25 years of age in Guanacaste;and (3) To identify the genetic basis for the oncogenicity of high-risk HPV types and variants. There is a gradient of oncogenic risk from the most oncogenic, HPV16, to less oncogenic types (e.g., HPV31/35/45/56) to non-oncogenic (e.g., HPV53/70) HPV types within the "oncogenic" species groups a.5-7, a9 and a11. We will infer full viral genome sequence from variant "haplotype" information. This data will be combined with pathologic state and/or case-control status from the results generated in the cohort studies to determine genotype-phenotype relationships using a variety of phylogenetic and analytic approaches. Overall the data will provide important information on phenotypic-genetic relationships.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA078527-15
Application #
8272685
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (J1))
Program Officer
Starks, Vaurice
Project Start
1998-07-24
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
15
Fiscal Year
2012
Total Cost
$567,757
Indirect Cost
$225,735
Name
Albert Einstein College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Harari, Ariana; Chen, Zigui; Rodríguez, Ana Cecilia et al. (2016) Cross-protection of the Bivalent Human Papillomavirus (HPV) Vaccine Against Variants of Genetically Related High-Risk HPV Infections. J Infect Dis 213:939-47
Frimer, Marina; Sun, Chang; McAndrew, Thomas et al. (2015) HPV16 CpG methyl-haplotypes are associated with cervix precancer and cancer in the Guanacaste natural history study. Gynecol Oncol 138:94-100
Mirabello, Lisa; Frimer, Marina; Harari, Ariana et al. (2015) HPV16 methyl-haplotypes determined by a novel next-generation sequencing method are associated with cervical precancer. Int J Cancer 136:E146-53
Chen, Zigui; de Freitas, Luciana Bueno; Burk, Robert D (2015) Evolution and classification of oncogenic human papillomavirus types and variants associated with cervical cancer. Methods Mol Biol 1249:3-26
Schiffman, Mark; Boyle, Sean; Raine-Bennett, Tina et al. (2015) The Role of Human Papillomavirus Genotyping in Cervical Cancer Screening: A Large-Scale Evaluation of the cobas HPV Test. Cancer Epidemiol Biomarkers Prev 24:1304-10
Van Doorslaer, Koenraad; DeSalle, Rob; Einstein, Mark H et al. (2015) Degradation of Human PDZ-Proteins by Human Alphapapillomaviruses Represents an Evolutionary Adaptation to a Novel Cellular Niche. PLoS Pathog 11:e1004980
Schiffman, M; Burk, R D; Boyle, S et al. (2015) A study of genotyping for management of human papillomavirus-positive, cytology-negative cervical screening results. J Clin Microbiol 53:52-9
Chen, Alyce A; Heideman, Daniëlle A M; Boon, Debby et al. (2014) Human papillomavirus 33 worldwide genetic variation and associated risk of cervical cancer. Virology 448:356-62
Harari, Ariana; Chen, Zigui; Burk, Robert D (2014) Human papillomavirus genomics: past, present and future. Curr Probl Dermatol 45:1-18
Zhang, Chuqing; Park, Jong-Sup; Grce, Magdalena et al. (2014) Geographical distribution and risk association of human papillomavirus genotype 52-variant lineages. J Infect Dis 210:1600-4

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