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Allele-specific Mutations Involved in the Pathogenesis of Endemic Gallbladder Carcinoma in Chile¹

Simmons Cancer Center [I. I. W., K. S., J. H., Y. K., A. K. V., A. F. G.] and Department of Pathology [I. I. W., A. K. V., J. A. S., A. F. G.], University of Texas Southwestern Medical Center, Dallas, Texas 75235, and Unit of Pathology, Faculty of Medicine, University La Frontera, Temuco, Chile [I. W., I. R.]

Although gallbladder carcinoma is one of the most frequent neoplasms in Chile, there is limited information about the molecular changes involved in its pathogenesis. We investigated the incidence of ras gene mutations and loss of heterozygosity (LOH) at the following genes/loci: p53, DCC, rb, 5q 3p, 8p, and 9p. We precisely microdissected 194 relevant areas from paraffin-embedded microslides from 25 gallbladder carcinomas and their accompanying nonneoplastic lesions (which were present in 15 cases) from patients in Chile. The specimens were analyzed by PCR-based assays for LOH, and we designed a RFLP method for ras mutations and immunohistochemistry for p53 protein overexpression. We determined that LOH at p53 (91%), 9p (50%), 8p (44%) and DCC (31%) are frequent events and that LOH at p53, 9p, and DCC are early events, while ras mutations and LOH at 3p, rb, and 5q occurred occasionally. LOH at p53 occurred more frequently and earlier than protein overexpression. The mean number of mutations present in invasive carcinomas was 2.1, and in six cases, LOH at the p53 gene was the sole mutation detected. The same allele was lost in 61 (93%) of 71 nonneoplastic foci as in the corresponding invasive carcinomas for all four mutations studied. The odds of this occurring by chance are 4 x 10^-15. Although clonality cannot be excluded, allelic loss appears to be highly directed, but the mechanism for allele-specific mutations remains to be determined.

¹ Supported in part by Grant 1-F05-TWO4982 from Fogarty International Center, a grant from the NIH, and Grant 1950657 from Agency for the Development of Science and Technology (FONDECYT), Chile.

² To whom requests for reprints should be addressed, at Simmons Cancer Center, UT-Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-8593.

Received 3/14/95. Accepted 5/ 5/95.

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