Microsatellite instability in gallbladder carcinoma: two independent genetic pathways of gallbladder carcinogenesis

Although the genetic basis for gallbladder carcinogenesis has not been clar ified, considerable evidence has shown that genetic alterations play an imp ortant role in the development and progression of human cancers. In this st udy, we analyzed 30 gallbladder carcinomas to investigate the role of genet ic alterations in their tumorigenesis, and to study correlations with their clinicopathological features. Tissue samples were obtained from 30 patient s with gallbladder carcinoma (11 men and 19 women; mean age, 62 years; age range, 38-80 years). Genomic DNAs were extracted from fresh tumor tissue. W e examined loss of heterozygosity (LOH) in the p53, APC, DCC, RE, and NM23- H1 gene regions by polymerase chain reaction (PCR)-LOH assay using an autom ated fluorescent DNA sequencer employing four microsatellite markers (p53, APC, DCC, NM23-H1). Five additional microsatellite markers were used for th e determination of microsatellite instability (MSI). LOH was found at p53 i n 9 of 15 informative cases (60%), at DCC in 10 of 22 (45%), at APC in 5 of 15 (33%), at RE in 1 of 8 (13%), and at NM23-H1 in 1 of 15 (7%). MSI was o bserved in 5 of 30 cases (17%) in at least one chromosomal loci of these ni ne microsatellite markers. None of the patients with MSI-positive tumors sh owed lymph node metastasis, and there was an inverse correlation between MS I and the presence of LOH in gallbladder carcinoma. These results suggest t hat there are two independent genetic pathways in gallbladder carcinogenesi s; that is, an MSI pathway and an LOH pathway.