JAMA Otol Logo Orlando 2013 AHNS Meeting Location
American Head & Neck Society
Annual Meeting, April 10-11, 2013
JW Marriott Grande Lakes
Orlando, Florida

During the
Combined Otolaryngology Spring Meeting
Tips on Using this Site
Locate an abstract by entering any author's surname into the search box.

Broaden your search by typing only a few letters of a keyword; do not append the wildcard “*” to a search string.

Type too small? In most browsers, press Control “+” to enlarge type size. Reset by pressing Control “0”.

Results. To view an abstract, click on a title within results. Presenters’ names are underlined among the list of authors.

Presentation: P009
Topic: Basic Science - Molecular / Cellular Biology
Type: Poster
Date: Wednesday - Thursday, April 10 - 11, 2013
Session: Designated Poster viewing times
Authors: Thomas J Ow, MD, MS, Vlad C Sandulache, MD, PhD, Daisuke Sano, MD, PhD, Pickering R Curtis, PhD, Heath D Skinner, MD, PhD, Mitchell Frederick, PhD, Wang Jing, PhD, Jiexin Wang, MS, Zhao Mei, MD, Tongxin Xie, MD, PhD, Harris M Thomas, PhD, Prystowsky B Michael, MD, PhD, Richard V Smith, MD, Lleras A Roberto, MS, Belbin J Thomas, PhD, Myers N Jeffrey, MD, PhD
Institution(s): Albert Einstein College of Medicine; Montefiore Medical Center; University of Texas, MD Anderson Cancer Center

 Background: The role of TP53 mutation in the development and progression of HNSCC has been well-established, and there is evidence that some types of TP53 mutations are strongly associated with poor outcomes. The following study explores changes in gene expression associated with TP53 mutation and aggressive tumor behavior in an orthotopic nude mouse xenograft model of HNSCC.
Methods: The HN30 and HN31 squamous carcinoma cell lines are an isogenic pair derived from a primary hypopharynx tumor and a lymph node metastasis, respectively. These lines differ in TP53 gene mutational status- HN30 is TP53 wild-type, and in HN31 TP53 carries two missense mutations. P53 expression was abrogated in both cell lines using sh-RNA (vs lentiviral control vector). Effects on p53 inhibition on tumor growth and metastasis were assessed in an orthotopic mouse xenograft model. Gene expression was examined in tumors derived from these cell lines using Affymetric U133A_2 arrays. After quality control across replicates (n=5 per cell line), RMA (Robust Multi-array Average) background correction, and quartile normalization, differentially expressed genes (DEG's) were filtered using Bonferroni correction. Gene lists were then overlapped to identify common hits among the cell lines, and DEG's were explored using literature mining.
Results: Knock-down of wild-type TP53 in HN30 resulted in a marked increase in cell proliferation in vitro, and significant increases in tumor volume and decreased survival in the orthotopic mouse model. Knockdown of mutant TP53 in HN31 resulted in minimal change in tumor growth and metastasis. Analysis of gene expression data identified several genes related to TP53 mutation and aggressive tumor growth: after stringent filtering, 6 genes were found to be consistently down-regulated (EFS, GALC, ICA1, DKFZp564I1922, CDKN1c, C14orf123) and 3 were consistently up-regulated (G1P2, SAA1, B2M). Particularly, CDKN1C, which is a negative regulator of cell proliferation, was identified as consistently down-regulated in the TP53-deficient and mutant lines. This gene and associated pathway members were further explored in a gene-expression database derived from patients with HPV-negative HNSCC in order to assess association with advanced T-stage and N-stage.
Conclusions: Loss of p53 expression or mutation is associated with aggressive tumor growth and an altered gene expression profile in our model system. Evaluation of this system suggests that cell proliferation may be significantly increased after loss of p53 and subsequent down-regulation of CDKN1C. Further work is underway to validate these observed associations, and to explore whether the genes we have identified are informative among patient samples.

JAMA Network Logo