Project Details
Description
Molecular characterization of human papillomavirus (HPV) associated oropharyngeal squamous cell
carcinomas (OPSCC) is genetically complex but has provided some promising insight into individual genetic
changes that contribute to improved cancer survival and tumor progression. However, current commercial
methods for detecting HPV in tumors by histopathology have shown poor sensitivity and specificity when
compared to the more labor intensive gold standard methods for detecting HPV RNA. Our research group has
recently developed a novel 22 CpG loci panel whose methylation status distinguishes between OPSCC with
and without HPV16 infections expressing the E6/E7 oncogenes. This has potential clinical relevance as
detection of HPV16 E6/E7 RNA in tumors has been associated with significantly improved cancer survival in
OPSCC. In this study, we propose to validate this host DNA methylation panel and test the novel epigenetic
events that may regulate key effector proteins, including for four panel loci downstream of the transcriptional
start site of CDKN2A(p16) that, despite being hypermethylated in tumor compared to normal tissues, are
associated with increased expression of the cellular gene. In this study, we propose to test and validate this
signature. We will: 1) test the hypothesis that changes in host DNA methylation status of the HPV panel have
functional consequences in altering expression of their corresponding genes; 2) the hypothesis that HPV viral
oncogenes E6 and E7 are sufficient to induce host DNA methylation and corresponding gene expression
changes seen in the HPV panel, including the novel changes observed for CDKN2A(p16); and 3) test the
clinical relevance of our HPV-driven methylation panel in clinical samples to determine which are most
predictive of clinical outcome. Combined with our experiments establishing functional and clinical relevance,
this study will lay the groundwork for future clinical studies to test clinical utility of an HPV-specific methylation
panel.
carcinomas (OPSCC) is genetically complex but has provided some promising insight into individual genetic
changes that contribute to improved cancer survival and tumor progression. However, current commercial
methods for detecting HPV in tumors by histopathology have shown poor sensitivity and specificity when
compared to the more labor intensive gold standard methods for detecting HPV RNA. Our research group has
recently developed a novel 22 CpG loci panel whose methylation status distinguishes between OPSCC with
and without HPV16 infections expressing the E6/E7 oncogenes. This has potential clinical relevance as
detection of HPV16 E6/E7 RNA in tumors has been associated with significantly improved cancer survival in
OPSCC. In this study, we propose to validate this host DNA methylation panel and test the novel epigenetic
events that may regulate key effector proteins, including for four panel loci downstream of the transcriptional
start site of CDKN2A(p16) that, despite being hypermethylated in tumor compared to normal tissues, are
associated with increased expression of the cellular gene. In this study, we propose to test and validate this
signature. We will: 1) test the hypothesis that changes in host DNA methylation status of the HPV panel have
functional consequences in altering expression of their corresponding genes; 2) the hypothesis that HPV viral
oncogenes E6 and E7 are sufficient to induce host DNA methylation and corresponding gene expression
changes seen in the HPV panel, including the novel changes observed for CDKN2A(p16); and 3) test the
clinical relevance of our HPV-driven methylation panel in clinical samples to determine which are most
predictive of clinical outcome. Combined with our experiments establishing functional and clinical relevance,
this study will lay the groundwork for future clinical studies to test clinical utility of an HPV-specific methylation
panel.
| Status | Finished |
|---|---|
| Effective start/end date | 9/18/13 → 8/31/16 |
ASJC
- Medicine(all)
- Dentistry(all)
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