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Department of Otolaryngology, Division of Head and Neck Cancer Research [M. P. R., P. C., D. S.], and Departments of Pathology [J. I. E.] and Urology [M. P. S.], Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and Environmental Carcinogenesis Laboratory, Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada [M. P. R.] and Division of Epidemiology and Cancer Prevention, British Columbia Cancer Research Centre, Vancouver, British Columbia, V5Z-1E6 Canada [M. P. R.]
Carcinoma in situ (CIS) of the urinary bladder is an aggressive lesion that frequently progresses to an invasive tumor, yet the underlying molecular changes in this lesion are largely unknown. In this study, we microdissected 31 cases of CIS and examined them for loss of heterozygosity (LOH) on 13 chromosomal arms. Twenty-nine microsatellite markers were chosen for this analysis based on their location in regions previously shown to be frequently lost in primary transitional cell carcinoma of the bladder. LOH of chromosome 9 was a frequent event in these samples, occurring in 77% of these lesions, with 19 of 31 cases showing deletion on the 9p arm (61%) and 17 of 28 cases displaying LOH on 9q (61%). Fine mapping at 9p21 demonstrated that CIS also displayed a high frequency of homozygous deletion surrounding the p16INK4A locus, like superficial papillary tumors, the other form of noninvasive lesion found in the bladder. However, loss of 14q (70%) was frequent in CIS yet extremely rare in papillary lesions (9%). Other chromosomal arms showing frequent LOH included 8p (65%), 17p (60%), 13q (56%), 11p (54%), and 4q (52%), whereas slightly lower frequencies of loss were observed for 11q (36%), 4p (32%), 3p (31%), 18q (29%), and 5q (20%). CIS lesions already possess many of the genetic alterations displayed by invasive transitional cell carcinomas, potentially accounting for the aggressive nature of these lesions.
1 Supported by a Collaborative Research Agreement with Oncor, Inc. (Gaithersburg, MD). Under an agreement between Oncor and the Johns Hopkins University, Dr. Sidransky is entitled to a share of sales royalty received by the University from Oncor. Under that agreement, the University and Dr. Sidranksky also have received Oncor stock which, under University policy, cannot be traded until 2 years after the first commercial sales of the products related to this research. Dr. Sidransky also serves as a member of the Scientific Advisory Board of Oncor's technology. The terms of this arrangement have been reviewed and approved by the University in accordance with its conflict of interest policies.
2 To whom requests for reprints should be addressed, at Department of Otolaryngology, Division of Head and Neck Cancer Research, Johns Hopkins School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205.
Received 8/ 2/95. Accepted 9/27/95.
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