This is a competing renewal proposal of translational research intended to advance the clinical use of molecular markers in squamous cell carcinoma of the head and neck. The centerpiece of the project is a large well characterized collection of tumor and histologically clear margin tissue collected in an Intergroup laboratory study. Subject accrual to this study is complete, but laboratory analysis and clinical data collection are ongoing. The primary goal of the study (specific aim #1) is to verify the utility of p53 molecular margin testing to assess risk of recurrence. To be clinically useful, molecular margin analysis must be rapid and applicable to all cases. We propose that high through-put p53 margin analysis using a novel Gap ligase chain reaction (GLCR) can be combined with methylation-specific PCR (MSP) for detection of tumor-specific promoter hypermethylation of target genes for tumors lacking p53 alterations make this possible. We will complete molecular assessment of all tumors in the cohort identifying both p53 mutations and methylation markers. Cases with tumors displaying p53 mutation will then undergo margin analysis using quantitative GLCR. Methylation markers will be tested in the p53 mutated cases to assess the concordance of the two markers in margin samples and to compare their predictive value. MSP will then be used to assess margins in p53 wild-type cases. A tissue microarray will be constructed to screen for methylation markers and explore p53-related molecular pathways (aim 2). The spectrum of target gene methylation and p53 mutations together with their downstream expression profiles will then be examined to refine their clinical predictive value. Expected correlations between clinical outcome and the presence of alterations in tumor and the detection of molecular residual disease in """"""""normal"""""""" margin and lymph node tissue will be tested (aim 3). This work makes maximal use of this invaluable collection of HNSCC specimens opening the door to accurate predictive assessment and a deeper understanding of tumor behavior.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CBSS (01))
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Shirazi, Yasaman
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Johns Hopkins University
Schools of Medicine
United States
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Bishop, Justin A; Westra, William H (2018) MYB Translocation Status in Salivary Gland Epithelial-Myoepithelial Carcinoma: Evaluation of Classic, Variant, and Hybrid Forms. Am J Surg Pathol 42:319-325
Bishop, Justin A; Cowan, Morgan L; Shum, Chung H et al. (2018) MAML2 Rearrangements in Variant Forms of Mucoepidermoid Carcinoma: Ancillary Diagnostic Testing for the Ciliated and Warthin-like Variants. Am J Surg Pathol 42:130-136
Bishop, Justin A; Andreasen, Simon; Hang, Jen-Fan et al. (2017) HPV-related Multiphenotypic Sinonasal Carcinoma: An Expanded Series of 49 Cases of the Tumor Formerly Known as HPV-related Carcinoma With Adenoid Cystic Carcinoma-like Features. Am J Surg Pathol 41:1690-1701
Rooper, Lisa M; Bishop, Justin A; Westra, William H (2017) Transcriptionally Active High-Risk Human Papillomavirus is Not a Common Etiologic Agent in the Malignant Transformation of Inverted Schneiderian Papillomas. Head Neck Pathol 11:346-353
Gaykalova, Daria A; Zizkova, Veronika; Guo, Theresa et al. (2017) Integrative computational analysis of transcriptional and epigenetic alterations implicates DTX1 as a putative tumor suppressor gene in HNSCC. Oncotarget 8:15349-15363
Guo, Theresa; Sakai, Akihiro; Afsari, Bahman et al. (2017) A Novel Functional Splice Variant of AKT3 Defined by Analysis of Alternative Splice Expression in HPV-Positive Oropharyngeal Cancers. Cancer Res 77:5248-5258
Rooper, Lisa M; Gandhi, Manoj; Bishop, Justin A et al. (2016) RNA in-situ hybridization is a practical and effective method for determining HPV status of oropharyngeal squamous cell carcinoma including discordant cases that are p16 positive by immunohistochemistry but HPV negative by DNA in-situ hybridization. Oral Oncol 55:11-6
Guo, Theresa; Gaykalova, Daria A; Considine, Michael et al. (2016) Characterization of functionally active gene fusions in human papillomavirus related oropharyngeal squamous cell carcinoma. Int J Cancer 139:373-82
Hayashi, Masamichi; Guerrero-Preston, Rafael; Sidransky, David et al. (2015) Paired box 5 methylation detection by droplet digital PCR for ultra-sensitive deep surgical margins analysis of head and neck squamous cell carcinoma. Cancer Prev Res (Phila) 8:1017-26
Gaykalova, Daria A; Manola, Judith B; Ozawa, Hiroyuki et al. (2015) NF-?B and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma. Int J Cancer 137:1879-89

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