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[1012] KLF6 Allelic Loss Predicts Poor Survival in Upper Aerodigestive Tract Squamous Cell Carcinomas (UADT-SCC)

M Brandwein, MS Texiera, N Schlecht, T Belbin, RV Smith, M Prystowsky, J Martignetti. Albert Einstein Medical College/Montefiore, Bronx, NY; Mount Sinai School of Medicine, NY, NY

Background: The Krppel-like factor 6 gene (KLF6) functions as a tumor suppressor gene involved in cell cycle control. We examined KLF6 genotype and RNA expression for UADT-SCC.
Design: Paraffin tumor/normal samples were studied in 81 cases of oral SCC. Four microsatellite markers spanning 17 Mb of 10p, and 2 KLF6-specific markers flanking KLF6 gene by 40Kb and 10Kb assessed KLF6 loss. After PCR and electrophoresis, data were analyzed with ABI Genescan and Genotyper software. The peak heights of the two alleles were compared; relative allele ratios 0.7 in at least two independent reactions was defined as consistent with loss. KLF6 LOH was positive only if at least one of the specific markers, KLF6 M1 and/or KLF6 M2, demonstrated allelic imbalance. RNA extracts of frozen samples from a second cohort with UADT-SCC including extra-oral sites, were studied for KLF6 wild-type (WT) and 3 splice variants (SV) by quantitative real-time PCR. Data were analyzed as continuous and discreet variables for WT and SV1, SV2, and SV3 alone, and as a ratio to WT.
Results: By KLF6 M1/KLF6 M2, 70 cases were informative and KLF6 LOH was present in 27% (19/70) of oral tumors. On survival analysis, KLF6 LOH was positively associated with time to disease progression (DP) (p=0.039,HR 2.5) and overall survival (OS) (p=0.001,HR 4.3) after correction for TN stage, and treatment. (Graph 1) Cox regression analysis for SV1/WT ratio using a median cutoff of >0.014 revealed an inverse relationship with locoregional recurrence (p = 0.101, HR 0.30) after correlation for TN stage and treatment.
Conclusions: KLF6 loss is a common event (27%) in UADT-SCC, and represents a significant prognosticator in multivariate analyses. Since LOH of the KLF6 locus would be expected to affect all KLF6 transcripts, taken together our LOH and expression data are particularly intriguing. Although preliminary, the observed inverse relationship between KLF6 and SV1 levels with locoregional recurrence and direct relationships of KLF6 (SV1-3) expression with survival highlights the finding that KLF6 isoforms may play an independent role in UADT-SCC prognosis.


Category: Head & Neck

Tuesday, March 27, 2007 11:15 AM

Platform Session: Section F, Tuesday Morning