KLF6 allelic loss is associated with tumor recurrence and markedly decreased survival in head and neck squamous cell carcinoma

Miriam S. Teixeira, Olga Camacho-Vanegas, Yolanda Fernandez, Goutham Narla, Analisa DiFeo, Bryant Lee, Tamara Kalir, Scott L. Friedman, Nicolas F. Schlecht, Eric M. Genden, Mark Urken, Margaret Brandwein-Gensler, John A. Martignetti

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29 Scopus citations

Abstract

The Krüppel-like transcription factor (KLF6) gene is a tumor suppressor gene (TSG) reported to be dysregulated and inactivated through loss of heterozygosity (LOH) and/or somatic mutation in a number of major human cancers. The aim of the present study was to examine KLF6 gene status and expression in head and neck squamous cell carcinomas (HNSCC). A collection of 81 well-characterized oral and oropharyngeal HNSCC samples were analyzed for evidence of KLF6 LOH and mutation and differences in expression patterns between normal and cancerous tissues and these findings were correlated with clinicopathological variables. We also tested the effect of KLF6 inhibition in HNSCC cell lines on proliferation and p21 expression. LOH was found in approximately 30% of cases and was strongly correlated with cancer progression, tumor recurrence and decreased patient survival. Overall, median survival of patients with LOH was less than half (19 vs. 41 months, p = 0.036, stratified on stage) than those without loss. Risk of death for patients with LOH was 8 times greater independent of tumor size, nodal status, tobacco smoking or treatment modality (HR 7.89, 95% CI: 1.9-32.4). Subsequent analyses revealed KLF6 mutations in only 2 of 20 samples, but altered subcellular protein localization in 64% of tumors. Targeted stable reduction of KLF6 in HNSCC cell lines increased cellular proliferation while decreasing p21 expression. Taken together, these findings suggest that KLF6 LOH represents a clinically-relevant biomarker predicting patient survival and tumor recurrence and that dysregulation of KLF6 function plays an important role in HNSCC progression.

Original languageEnglish (US)
Pages (from-to)1976-1983
Number of pages8
JournalInternational Journal of Cancer
Volume121
Issue number9
DOIs
StatePublished - Nov 1 2007

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Keywords

  • HNSCC
  • Haploinsufficiency
  • KLF6
  • Loss of heterozygosity
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Teixeira, M. S., Camacho-Vanegas, O., Fernandez, Y., Narla, G., DiFeo, A., Lee, B., Kalir, T., Friedman, S. L., Schlecht, N. F., Genden, E. M., Urken, M., Brandwein-Gensler, M., & Martignetti, J. A. (2007). KLF6 allelic loss is associated with tumor recurrence and markedly decreased survival in head and neck squamous cell carcinoma. International Journal of Cancer, 121(9), 1976-1983. https://doi.org/10.1002/ijc.22926