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Amplicon Mapping and Expression Profiling Identify the Fas-Associated Death Domain Gene as a New Driver in the 11q13.3 Amplicon in Laryngeal/Pharyngeal Cancer

Authors' Affiliations: Departments of ¹ Pathology, ² Epidemiology and Statistics, ³ Otorhinolaryngology, Head and Neck Surgery, ⁴ Radiation Oncology, and ⁵ Human Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; ⁶ Department of Otolaryngology, Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain; Departments of ⁷ Pathology and ⁸ Head and Neck Oncology and Surgery, the Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Amsterdam, the Netherlands; and ⁹ Department of Otolaryngology/Head and Neck Surgery, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands

Requests for reprints: Ed Schuuring, Department of Pathology, University Medical Center Groningen, P.O. Box 30001, 9700 RB, Groningen, the Netherlands. Phone: 31-50-361-9623; Fax: 31-50-361-9107; E-mail: e.schuuring{at}path.umcg.nl.

Purpose: Amplification of the 11q13 region is a frequent event in human cancer. The highest incidence (36%) is found in head and neck squamous cell carcinomas. Recently, we reported that the amplicon size in 30 laryngeal and pharyngeal carcinomas with 11q13 amplification is determined by unique genomic structures, resulting in the amplification of a set of genes rather than a single gene.

Experimental Design: To investigate which gene(s) drive the 11q13 amplicon, we determined the smallest region of overlap with amplification and the expression levels of all genes within this amplicon.

Results: Using array-based comparative genomic hybridization analysis, we detected a region of 1.7 Mb containing 13 amplified genes in more than 25 of the 29 carcinomas. Quantitative reverse transcription-PCR revealed that overexpression of 8 potential driver genes including, cyclin D1, cortactin, and Fas-associated death domain (FADD), correlated significantly with DNA amplification. FADD protein levels correlated well with DNA amplification, implicating that FADD is also a candidate driver gene in the 11q13 amplicon. Analysis of 167 laryngeal carcinomas showed that increased expression of FADD (P = 0.007) and Ser¹⁹⁴ phosphorylated FADD (P = 0.011) were associated with a worse disease-specific survival. FADD was recently reported to be involved in cell cycle regulation, and cancer cells expressing high levels of the Ser¹⁹⁴ phosphorylated isoform of FADD proved to be more sensitive to Taxol-induced cell cycle arrest.

Conclusion: Because of the frequent amplification of the 11q13 region and concomitant overexpression of FADD in head and neck squamous cell carcinomas, we hypothesize that FADD is a marker to select patients that might benefit from Taxol-based chemoradiotherapy.