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Identification of a Novel Region of Homozygous Deletion on Chromosome 9p in Squamous Cell Carcinoma of the Lung: The Location of a Putative Tumor Suppressor Gene¹

St. Mary's Hospital Cancer Research Institute, Grand Junction, Colorado 81502 [J. S. W., J. T. O., K. F., G. S., M. W. A.]; The University of Colorado Health Science Center, Denver, Colorado 80262 [W. A. F., M. V-G., K. R., H. D., R. G.]; Department of Otolaryngology-Head and Neck Surgery, John Hopkins University School of Medicine, Baltimore, Maryland 21205 [S. A., D. S.]; and Department of Biochemistry and Molecular Biology and the Institute for Genetic Medicine, University of Southern California, Los Angeles, California 90033 [J. W. F.]

Cytogenetic and molecular studies have implied the presence of tumor suppressor genes (TSGs) on chromosome 9p that are critical in the development of lung and other cancers. The p16/CDKN2 gene, a cyclin dependent kinase inhibitor, is a well-defined TSG on 9p21. Although the frequency of mutations in the p16/CDKN2 gene has been detected in approximately 30% of non-small cell lung cancer, loss of heterozygosity on 9p has been observed in greater than 70% of non-small cell lung cancers. These and other deletion mapping studies have suggested the existence of additional TSGs on 9p. This study examined chromosome 9p for TSG loci by analyzing 23 squamous cell carcinomas of the lung with 21 microsatellite markers. Loss of heterozygosity was detected in all of the tumors, and homozygous deletions of the p16/CDKN2 locus were observed in 6 of the 23 tumors (26%). In addition, a novel region of homozygous deletion was detected in six tumors (26%) at D9S126, approximately 2.5 cM proximal to p16/CDKN2. A single tumor contained a homozygous deletion at both the p16/CDKN2 locus and the D9S126 locus. The possibility of homozygous loss was confirmed by multiplex PCR using both the D9S126 marker and a chromosome 9p control marker. Fluorescence in situ hybridization analysis with P1 and cosmid probes containing D9S126 also confirmed these data. The minimum region of homozygous deletion was determined by testing markers immediately proximal and distal to the D9S126 region. The data identify a homozygous loss on the short arm of chromosome 9 suggesting the presence of a novel TSG locus, proximal to p16/CDKN2 and located between D9S265 and D9S259.

¹ This work was supported by United States Department of Energy Grant FG03-94ER61842 (to J. S. W., J. T. O., G. S., and M. W. A.) and NIH Grants CA-58187 Specialized Program of Research Excellence (SPORE) in Lung Cancer (to J. S. W., W. A. F., M. V-G., H. D., R. G., and M. W. A.), CA-58184 SPORE in Lung Cancer (to S. A. and S. D.), and CA-66021 (to J. W. F.).

² To whom requests for reprints should be addressed, at Department of Environmental Health, University of Cincinnati, Cincinnati, OH. 45267-0056. Phone: (513) 558-5724.

Received 8/30/96. Accepted 11/15/96.

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