Nooshin Hashemi Sadraei

Comparative molecular profiling of HPV‐induced squamous cell carcinomas

Approximately 5% of all cancer incidences result from human papillomavirus (HPV) infection. HPV infection most commonly leads to cancers of the anogenital region or oropharynx. It is unknown whether different HPV‐mediated cancers collectively share a molecular signature and it is important to determine if there are targetable alterations common to different types of HPV‐positive tumors. We analyzed 743 p53 wild‐type samples of anal, cervical, oropharyngeal, and vulvar squamous cell carcinomas which underwent multiplatform testing at a commercial molecular profiling service. Expression of 24 proteins was measured by immunohistochemistry (IHC), mutation of 48 genes was determined by next‐generation and Sanger sequencing, and copy number alteration for six genes was determined by in situ hybridization. The four cohorts had remarkably similar molecular profiles. No gene had a statistically significant difference in mutation frequency or copy number change between the four different types of squamous cell carcinomas. The only significant differences between cohorts were frequency of ERCC1 and SPARC loss as determined by IHC. In all four cancer types, oncogene mutation and PD‐L1 expression was relatively infrequent. The most commonly mutated gene was PIK3CA, with mutations most often affecting the helical domain of the protein and accompanied by concurrent lack of PTEN expression. Loss of MGMT and RRM1 was common among the four cohorts and may be predictive of response to cytotoxic therapies not currently being used to treat these cancer types. The similar molecular profiles of the four cohorts indicate that treatment strategies may be similarly efficacious across HPV‐positive cancers.

Decreased plasma DEK Oncogene Levels Correlate with p16-Negative Disease and Advanced Tumor Stage in a Case–Control Study of Patients with Head and Neck Squamous Cell Carcinoma

Head and neck cancer (HNC) remains the sixth most common malignancy worldwide and survival upon recurrence and/or metastasis remains poor. HNSCC has traditionally been associated with alcohol and nicotine use, but more recently the Human Papilloma Virus (HPV) has emerged as a favorable prognostic risk factor for oropharyngeal HNSCC. However, further stratification with additional biomarkers to predict patient outcome continues to be essential. One candidate biomarker is the DEK oncogenic protein, which was previously detected in the urine of patients with bladder cancer and is known to be secreted by immune cells such as macrophages. Here, we investigated if DEK could be detected in human plasma and if DEK levels correlated with clinical and pathological variables of HNSCC. Plasma was separated from the peripheral blood of newly diagnosed, untreated HNSCC patients or age-matched normal healthy controls and analyzed for DEK protein using ELISA. Plasma concentrations of DEK protein were lower in p16-negative tumors compared to both normal controls and patients with p16-positive tumors. Patients with lower plasma concentrations of DEK were also more likely to have late stage tumors and a lower white blood cell count. Contrary to previously published work demonstrating a poor prognosis with high intratumoral DEK levels, we show for the first time that decreased concentrations of DEK in patient plasma correlates with poor prognostic factors, including HPV-negative status as determined by negative p16 expression and advanced tumor stage.

Abstract 50: Plasma concentrations of the DEK oncogene correlate with pathological variables in a case-control study of patients with HNSCC

Background: Head and neck squamous cell carcinoma (HNSCC) has traditionally been associated with alcohol and nicotine use, but more recently the Human Papilloma Virus (HPV) has emerged as a favorable prognostic risk factor for oropharyngeal HNSCC. However, further stratification with additional biomarkers to predict patient outcome continues to be essential. One candidate biomarker is the chromatin remodeling DEK protein, which is both an auto-antigen in autoimmune diseases and an oncogene in epithelial tissues. DEK is secreted by stimulated macrophages and neutrophils and was previously detected in the urine of patients with bladder cancer. Previously, we have reported that DEK mRNA and protein is upregulated in HNC tumor tissue and higher DEK levels are associated with poor prognoses in many types of solid tumors. We hypothesized that DEK could be detected in the plasma of HNC patients, either due to secretion from the tumor or as part of the antitumor immune response, and therefore may be a biomarker for disease status. Methods: We recruited 38 newly diagnosed HNSCC patients and 37 age-matched normal healthy controls into the study. Plasma isolated from peripheral blood was subjected to DEK specific ELISA and DEK concentration levels were compared to levels found in normal controls, and to clinical and pathological variables. Results: We show for the first time that DEK can be detected in human plasma. We did not find an association between DEK plasma concentrations and variables including sex, age, race, or drinking/smoking status. However, we detected decreased concentrations of DEK in HNC patients with p16-negative disease and in patients with larger tumor sizes, indicating an association between DEK levels and known prognostic markers. In addition, HNC patients with lower DEK concentrations had a decreased white blood cell count, largely due to differences in lymphocyte and eosinophil counts. This direct association between plasma DEK levels and white blood cell count was independent of p16 status. Conclusions: Together, the data suggest that lower levels of DEK in HNC patient plasma may be predictive of poor outcome. This is in direct contrast to what is observed with intratumoral levels of DEK protein, in which higher levels of DEK expression are an independent factor predicting poor prognosis. Future studies will investigate the role that secreted DEK, such as that found in the plasma, may have in the antitumor immune response. Citation Format: Trisha Wise-Draper, Arun Sendilnathan, Sarah Palackdharry, Nicholas Pease, Julianne Qualtieri, Randy Butler, Nooshin Hashemi Sadraei, John C. Morris, Yash Patil, Keith Wilson, Jonathan Mark, Keith Casper, Vinita Takiar, Adam Lane, Lisa M. Privette Vinnedge. Plasma concentrations of the DEK oncogene correlate with pathological variables in a case-control study of patients with HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 50.