Genome-wide allelotyping analysis reveals multiple sites of allelic loss in gallbladder carcinoma

Although gallbladder carcinoma (GBC) is a highly malignant neoplasm, there is very limited information about the molecular changes involved in its pat hogenesis. To identify the chromosomal locations of putative tumor suppress or gene loci Involved in the pathogenesis of GBC, we conducted a genome-wid e allelotyping or loss of heterozygosity (LOH) analysis of GBCs. Microdisse cted tissue from 24 archival GBCs and their matched control DNAs were analy zed for PCR-based LOH using 169 microsatellite markers spanning all nonacro centric autosomal arms and the X chromosome. The chromosomal arms with the greatest frequencies of LOH (greater than or equal to 60%) were 3p, 6q, 7q, 8p, 9p, 9q, 11q, 12q, 17p, 18q, 19p, 22q, and Xq. The average fractional a llele loss index in GBC cases was high (0.43) and frequent breakpoints were detected in gallbladder tumors. Of interest, 21 different regions of frequ ent LOH (hot spots) defined as greater than or equal to 50% for individual GBC samples were detected in this neoplasm, nearly half of them confined to one microsatellite marker. We conclude that in GBC at least 21 chromosomal regions with frequent allele losses are involved, suggesting that several putative tumor suppressor genes are inactivated in its pathogenesis. Overal l, these data provide global estimates of the extent of genetic changes lea ding to GBC and will be useful for the identification of new tumor suppress or genes and for multiple new markers for translational research.