KLF6 allelic loss is associated with tumor recurrence and markedly decreased survival in head and neck squamous cell carcinoma.
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.
Teixeira
Miriam S
MS
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY.
Camacho-Vanegas
Olga
O
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY.
Fernandez
Yolanda
Y
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY.
Narla
Goutham
G
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY.|Department of Medicine, Mount Sinai School of Medicine, New York, NY.
DiFeo
Analisa
A
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY.
Lee
Bryant
B
Department of Otolaryngology, Mount Sinai School of Medicine, New York, NY.
Kalir
Tamara
T
Department of Pathology, Mount Sinai School of Medicine, New York, NY.
Friedman
Scott L
SL
Department of Medicine, Mount Sinai School of Medicine, New York, NY.
Schlecht
Nicolas F
NF
Department of Epidemiology and Population Health, Division of Epidemiology and Medicine, Division of Oncology, Albert Einstein College of Medicine, Bronx, NY.
Genden
Eric M
EM
Department of Otolaryngology, Mount Sinai School of Medicine, New York, NY.|Immunobiology Institute, Mount Sinai School of Medicine, New York, NY.|Head and Neck Cancer Center, Mount Sinai School of Medicine, New York, NY.
Urken
Mark
M
Department of Otolaryngology, Mount Sinai School of Medicine, New York, NY.
Brandwein-Gensler
Margaret
M
Department of Pathology, Mount Sinai School of Medicine, New York, NY.
Martignetti
John A
JA
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY.|Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D015996:Survival Rate
C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins