Head and neck cancer is often treated with surgical excision as the first therapeutic method. Local disease control and eventual survival are closely associated with achievement of clear surgical margins. However, many patients suffer recurrence of tumor despite surgery with histologically clear margins. Over a decade ago, we showed that molecular evaluation for the presence of rare tumor cells in histologically clear resection margins was associated with a high risk of local recurrence. However, this approach has not been adopted in routine clinical practice because of the technically challenging nature of the molecular probing of margin DNA. The overall goal of this proposal is to complete the steps necessary to demonstrate that molecular assessment of surgical resection margins is a valuable and feasible tool for generalized clinical use in the management of head and neck mucosal malignancies. The platform for this endeavor is a high quality clinical sample and corresponding data set from the ECOG E4393/RTOG 9614 head and neck margin study of which Dr. Koch is PI. The project has three specific aims: (1) Verification of a panel of tumor-specific molecular markers as robust and universal for HNSCC surgical resection margin analysis. Hypermethylation of four genes identified in the Hopkins head and neck SPORE shows great promise for this panel. (2) Molecular margin analysis for prediction of outcome: Rigorous assessment of the utility of molecular margin analysis using this large, well characterized cohort of HNSCC tumors and margins will be followed by a search for correlates between molecular and clinical outcome. (3) Determine the clinical correlates of tumor-specific molecular alterations. This last aim builds on our recent successful identification of a high risk subpopulation of mutations of TP53 in this cohort of HNSCC tumors capitalizing on its large size and mature outcome information. With the successful accomplishment of these steps, adoption of the practice of molecular margin analysis by cancer centers with a substantial volume of HNSCC cases is anticipated.

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Project summary: We plan to complete measures necessary to demonstrate the clinical efficacy and feasibility of molecular assessment of tumor resection margins in treatment of head and neck cancer. A large, well characterized cohort of tumor and margin samples will be probed for a panel of tumor-specific promoter hypermethylation markers. Clinical correlates of molecular findings in tumor and margins will be evaluated by the ECOG data resource center.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Cancer Biomarkers Study Section (CBSS)
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Venkatachalam, Sundaresan
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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
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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
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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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