Fez1/Lzts1 alterations in gastric carcinoma

Purpose: Loss of heterozygosity (LOH) involving the short arm of chromosome 8 (8p) is a common feature of the malignant progression of human tumors, i ncluding gastric cancer, We have cloned and mapped a candidate tumor suppre ssor gene, FEZ1/LZTS1, to 8p22, Here we have analyzed whether FEZ1/LZTS1 al terations play a role in the development and progression of gastric carcino ma. Experimental Design: We examined Fez1/LZTS1 expression in 8 gastric carcino ma cell lines by Western blot, and in 88 primary gastric carcinomas by immu nohistochemistry. Twenty-six of these 88 primary gastric carcinomas were al so microdissected and tested for LOH at the FEZ1/LZTS1 locus and for mutati on of the FEZI/LZTSI gene. Furthermore, we studied the FEZ1/LZTS1 gene regu lation and transcriptional control and the methylation status of the 5' reg ion of the gem in ah 8 gastric carcinoma cell lines. Results: Fez1/Lzts1 protein was barely detectable in all of the gastric can cer cell lines tested and was absent or significantly reduced in 39 of the 88 (44.3%) gastric tarcinomas analyzed by immunohistochemistry,,vith a sign ificant correlation (P < 0.001) to diffuse histotype, DNA allelotyping anal ysis showed allelic loss in 3 of 17 (18%) and microsatellite instability in 4 of 17 (23.5%) cases informative for D8S261 at the FEZ1/LZTS1 locus. When we compared the presence of LOH with Fez1/Lzts1 expression, we found loss of protein expression in all three of the tumors with allelic imbalance at D8S261, A missense mutation was detected in one case that did not express F ez1/Lzts1, Hypermethylation of the CpG island flanking the Fez1/Lzts1 promo ter was evident in six of the eight tell lines examined as well as in the n ormal control. Conclusions: Our findings support FEZI/LZTSI as a candidate tumor suppresso r gene at gp in a subtype of gastric cancer and suggest that its inactivati on is attributable to several factors including genomic deletion and methyl ation.