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Division of Head and Neck Cancer Research, Department of Otolarynology-Head and Neck Surgery, The Johns Hopkins University, Baltimore, Maryland 21205-2196 [S. I. P., L. W., J. J., D. S.], and The Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Departments of Medicine, Genetics, and Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6148 [G. S. W., N. O., W. S. E-D.]
The chromosomal region 8p21 contains a number of putative tumor suppressor genes and is a frequent site of translocations in head and neck cancers. Recently, a novel tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor gene, KILLER/DR5, a member of the tumor necrosis factor receptor family, was identified as a potential mediator in p53-dependent apoptosis and mapped to 8p21 by fluorescence in situ hybridization. We have determined the genomic structure of KILLER/DR5 and performed sequence analysis of all 10 coding exons in 20 primary head and neck cancers with allelic loss of chromosome 8p. To screen for a subset of mutations localized to the functional cytoplasmic death domain, we sequenced this region in an additional 40 primary head and neck cancers. We found two alterations in this domain, including a 2-bp insertion at a minimal repeat site, introducing a premature stop codon and resulting in a truncated protein. This KILLER/DR5 mutation was also present in the germ line of the affected patient, and the tumor did not have a p53 mutation by sequence analysis. Transfection studies in head and neck squamous cell carcinoma and colon and ovarian carcinoma cell lines revealed loss of growth-suppressive function associated with the tumor-derived KILLER/DR5 truncation mutant. These observations provide the first evidence for mutation of a TRAIL death receptor gene in a human cancer, leading to loss of its apoptotic function.
1 Supported by Specialized Program of Research Excellence Lung Cancer Grant CA-58184-01 (to D. S.) and by funds from the University of Pennsylvania Comprehensive Cancer Center (to W. S. E-D.), W. S. E-D. is an Assistant Investigator of the Howard Hughes Medical Institute.
2 S. I. P. and G. S. W. contributed equally to this work.
3 To whom requests for reprints should be addressed, at Division of Head and Neck Cancer Research, Department of Otolarynology-Head and Neck Surgery, The Johns Hopkins University, 720 Rutland Ave., Ross 818, Baltimore, MD 21205-2196. E-mail: dsidrans@welchlink.welch.jhu.edu.
Received 4/29/98. Accepted 6/30/98.
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