INACTIVATION OF SMAD4 IN GASTRIC CARCINOMAS

Allelic loss of chromosome 18q has been noted in intestinal type gastr ic adenocarcinomas. Smad4 is a gene located at 18q that was recently c loned in humans and found to be significantly altered in pancreatic ca ncers, We sought to determine whether Smad4 genetic alterations played a significant role in gastric tumorigenesis by studying 35 gastric ad enocarcinomas of all histopathological types and pathological stages, Microdissected specimens were used for mutational analysis of Smad4 at the nucleotide level, including the entire coding region and intron/e xon boundaries, Allelic imbalance was also analyzed at the Smad4 locus using two nearby microsatellite markers. One case of apparent biallel ic inactivation of Smad4 was found in our study of 35 gastric carcinom as, A nonsense point mutation at codon 334 was demonstrated, which, si milar to other Smad4 mutations, is predicted to truncate the conserved COOH-terminal domain of this protein, This Smad4 C to T transition mu tation was proven to be somatically acquired, Allelic loss was also no ted on chromosome 18q at a marker near Smad4 in this mutated gastric c ancer, apparently producing complete inactivation of Smad4 in this tum or, Significant 18q allelic loss (56% of 34 informative cases) was not ed in our gastric carcinomas using microsatellite markers near the Sma d4 locus, regardless of histological subtype or pathological stage, Ad ditionally, three cases of microsatellite instability were observed. T hus, Smad4 inactivation was noted in our gastric carcinomas; however, this event was rare, The frequent loss of chromosomal arm 18q observed in gastric cancers suggests the presence of other tumor suppressor ge nes in this region that are involved in gastric tumorigenesis. Further studies are needed to identify these other targets of inactivation du ring gastric cancer development.