DIVERGENT ROLE OF INTERMEDIATE FILAMENTS IN HPVPOSITIVE AND

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DIVERGENT ROLE OF INTERMEDIATE FILAMENTS IN HPVPOSITIVE AND HPVNEGATIVE HEAD AND NECK SQUAMOUS CELL

DIVERGENT ROLE OF INTERMEDIATE FILAMENTS IN HPVPOSITIVE AND HPVNEGATIVE HEAD AND NECK SQUAMOUS CELL CARCINOMA Nikol Mladkova, MD, Ph. D, MPH Dukagjin Blakaj, MD, Ph. D Department Of Radiation Oncology Arthur G. James Cancer Hospital Ohio State University nikol. mladkova@osumc. edu • Abstract: • OBJECTIVE: Head and neck cancer (HNC) represents a diverse group of malignancies associated with smoking, alcohol consumption and HPV infection. HPV-associated malignancies have generally better prognosis compared to tumor lacking HPV. Intermediate filaments represent a type of cytoskeletal elements involved in cellular structural support and the regulation of critical cellular processes such as growth, proliferation and apoptosis. METHODS: We explored the gene expression of all intermediate filaments genes (n=73) in 72 HPV-positive tumors and 415 HPV-negative HNC tumors available in the TCGA. We divided the expression of intermediate filaments genes into high or low by median expression, and correlated this value with overall and progression-free survival. Association was considered significant if p value was less than 0. 05. RESULTS: In HPV-negative tumors, higher expression of keratin 75 and 13 resulted in improved progression-free survival (PFS). Keratin 13 levels negatively correlated with EMT-promoting genes SNAI 1 and SNAI 2. Conversely, higher expression of keratin 8, 18, and 20 was associated with worse OS. In HPV positive tumors, on the other hand, higher expression of BFSP 1 was associated with worse OS and negatively correlated with TP 53 levels. Higher expression of syncoilin and NEFL also lead to worse survival, while higher levels of keratin 15 and 38 was associated with improved survival. CONCLUSIONS: Intermediate filaments are likely intertwined in key regulatory processes that pertain to cancer progression and potential response to treatment, and appear to have a divergent role based on the presence of HPV infection. Pending further validation, these may represent practical histological prognostic markers.

BACKGROUND • Head and neck squamous cell carcinoma (HNSCC): distinct etiology for HPV-negative tumors

BACKGROUND • Head and neck squamous cell carcinoma (HNSCC): distinct etiology for HPV-negative tumors (alcohol consumption, smoking) and HPV-positive tumors (HPV 16 infection) • Distinct prognosis for each subgroup of HNSCC • Intermediate filaments (IFs): cytoskeletal elements of ~ 10 nm in diameter, with increasingly described function ranging from mechanical support to cell motility • Hypothesis: The expression of IFs plays a prognostic role in HPV- and HPV+ HNSCC nikol. mladkova@osumc. edu

METHODS • We explored the gene expression of all intermediate filaments genes (n=73) based

METHODS • We explored the gene expression of all intermediate filaments genes (n=73) based on normalized RNAsequencing counts in 72 HPV-positive tumors and 415 HPV-negative HNC tumors available in the TCGA • We divided the expression of intermediate filaments genes into high or low by median expression • This value was correlated with overall and progression-free survival using cox-proportional hazard • Association was considered significant if p value was less than 0. 05 nikol. mladkova@osumc. edu

RESULTS IN HPV+ TUMORS High expression of BFSP 1 was associated with worse OS

RESULTS IN HPV+ TUMORS High expression of BFSP 1 was associated with worse OS and negatively correlated with TP 53 levels, and showed significant negative correlation with TP 53 I 11, a known EMT suppressor (Figure 1) Figure 1. Worse OS with increased BFSP 1 levels and decreased levels of TR 53 I 11 Higher expression of syncoilin and NEFL also lead to worse OS survival Higher levels of keratin 15 and 38 was associated with improved survival (Figure 2) nikol. mladkova@osumc. edu Figure 2. Improved OS with increased Keratin 38 levels and improved PFS with increased KRT 15 levels

RESULTS IN HPV- TUMORS Figure 3. Increased keratin 75 and Keratin 13 levels are

RESULTS IN HPV- TUMORS Figure 3. Increased keratin 75 and Keratin 13 levels are associated with Improved PFS In HPV-negative tumors, higher expression of keratin 75 and 13 resulted in improved progression-free survival (PFS) (Figure 3) Keratin 13 levels negative correlated with EMT-promoting genes SNAI 1 and SNAI 2 (Figure 4). Higher expression of keratin 8, 18, and 20 was associated with worse OS. nikol. mladkova@osumc. edu Figure 4. Increased Keratin 13 levels are negatively correlated with EMT promoters SNAI 1 and SNAI 2

CONCLUSIONS • Intermediate filaments are likely intertwined in key regulatory processes that pertain to

CONCLUSIONS • Intermediate filaments are likely intertwined in key regulatory processes that pertain to cancer progression and potential response to treatment • These appear to have a divergent role based on the presence of HPV infection. • Pending further validation, these may represent practical histological prognostic markers. nikol. mladkova@osumc. edu