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Maria J. Worsham, PhD; Kang Mei Chen, MD; Venkata Meduri, MD; Anders O. H. Nygren, PhD; Abdellatif Errami, PhD; Jan P. Schouten, PhD; Michael S. Benninger, MD

Arch Otolaryngol Head Neck Surg. 2006;132:668-677.

Objective  To examine the promoter methylation status of the 22 cancer genes and their contribution to disease progression in 6 head and neck squamous cell carcinoma (HNSCC) cell lines.

Design  A panel of 41 gene probes, designed to interrogate 35 unique genes with known associations to cancer including HNSCC, was interrogated for alterations in gene copy number and aberrant methylation status (22 genes) using the methylation-specific multiplex ligation-dependent probe amplification assay.

Subjects  Primary (A) and recurrent or metastatic (B) HNSCC cell lines UMSCC-11A/11B, UMSCC-17A/17B, and UMSCC-81A/81B are described.

Results  Nine genes, TIMP3, APC, KLK10, TP73, CDH13, IGSF4, FHIT, ESR1, and DAPK1, were aberrantly methylated. The most frequently hypermethylated genes were APC and IGSF4, observed in 3 of 6 cell lines, and TP73 and DAPK1, observed in 2 of 6. For KLK10 and IGSF4, TIMP3 and FHIT, and TP73, in UMSCC-11B, UMSCC-17B, and UMSCC-81B, respectively, promoter hypermethylation was a disease progression event, indicating complete abrogation of tumor suppressor function for KLK10, IGSF4, and TIMP3 and gene silencing of 1 of 2 copies of TP73. Hypermethylation of IGSF4, TP73, CDH13, ESR1, DAPK1, and APC were primary events in UMSCC-17A.

Conclusions  Gene silencing through promoter hypermethylation was observed in 5 of 6 cell lines and contributed to primary and progressive events in HNSCC. In addition to genetic alterations of gains and losses, epigenetic events appear to further undermine a destabilized genomic repertoire in HNSCC.

Author Affiliations: Department of Otolaryngology–Head and Neck Surgery and Research Division, Henry Ford Health System, Detroit, Mich (Drs Worsham, Chen, Meduri, and Benninger); and MRC-Holland, Amsterdam, the Netherlands (Drs Nygren, Errami, and Schouten).

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