Our recent genome-wide allelotyping analysis of gallbladder carcinoma identified 3p, 8p, 9q and 22q as chromosomal regions with frequent loss of heterozygosity. The present study was undertaken to more precisely identify the presence and location of regions of frequent allele loss involving those chromosomes in gallbladder carcinoma. Microdissected tissue from 24 gallbladder carcinoma were analysed for PCR-based loss of heterozygosity using 81 microsatellite markers spanning chromosome 3p (n=26), 8p (n=14), 9q (n=29) and 22q (n=12) regions. We also studied the role of those allele losses in gallbladder carcinoma pathogenesis by examining 45 microdissected normal and dysplastic gallbladder epithelia accompanying gallbladder carcinoma, using 17 microsatellite markers. Overall frequencies of loss of heterozygosity at 3p (100%), 8p (100%), 9q (88%), and 22q (92%) sites were very high in gallbladder carcinoma, and we identified 13 distinct regions undergoing frequent loss of heterozygosity in tumours. Allele losses were frequently detected in normal and dysplastic gallbladder epithelia. There was a progressive increase of the overall loss of heterozygosity frequency with increasing severity of histopathological changes. Allele losses were not random and followed a sequence. This study refines several distinct chromosome 3p, 8p, 9q and 22q regions undergoing frequent allele loss in gallbladder carcinoma that will aid in the positional identification of tumour suppressor genes involved in gallbladder carcinoma pathogenesis. British Journal of Cancer (2002) Gallbladder carcinoma (GBC) is a relatively uncommon neoplasm which demonstrates considerable geographic and gender variation in incidence (Albores-Saavedra and Henson, 2000). For unknown reasons, it is one of the most frequent neoplasms in Chile, where it is the leading cause of cancer deaths in females (Lazcano-Ponce et al, 2001). It has been well established that invasive GBC is preceded by preneoplastic lesions, including dysplastic changes of the gallbladder epithelium (Albores-Saavedra and Henson, 2000). There is a very limited information about the molecular changes involved in the pathogenesis of GBC (Wistuba and Albores-Saavedra, 1999).It is now well recognised that tumourigenesis is a multistep process resulting from the accumulation of sequential genetic alterations (Fearon and Vogelstein, 1990). In addition to oncogene activation, inactivation of tumour suppressor genes (TSGs) has been shown to play an important role in tumourigenesis (Fearon and Vogelstein, 1990). Allelic loss, manifested as loss of heterozygosity (LOH) at polymorphic loci, is recognised as a hallmark of tumour suppressor genes, whose other allele is inactivated by point mutations or by some other mechanism (Knudson, 1985). Thus, the finding of chromosomal regions with frequent incidence of LOH in a neoplasm suggests that those regions may harbour one or more TSGs.Our recent genome-wide allelotyping analysis on GBC indicated that allelic losses at multiple sites of the genome are freque...
