title: Fez1/lzts1 alterations in gastric carcinoma.
abstract: OBJECTIVE
  Loss of heterozygosity (LOH) involving the short arm of chromosome 8 (8p) is a common feature of the malignant progression of human tumors, including gastric cancer. We have cloned and mapped a candidate tumor suppressor gene, FEZ1/LZTS1, to 8p22. Here we have analyzed whether FEZ1/LZTS1 alterations play a role in the development and progression of gastric carcinoma.
  
  
  METHODS
  We examined Fez1/Lzts1 expression in 8 gastric carcinoma cell lines by Western blot, and in 88 primary gastric carcinomas by immunohistochemistry. Twenty-six of these 88 primary gastric carcinomas were also microdissected and tested for LOH at the FEZ1/LZTS1 locus and for mutation of the FEZ1/LZTS1 gene. Furthermore, we studied the FEZ1/LZTS1 gene regulation and transcriptional control and the methylation status of the 5' region of the gene in all 8 gastric carcinoma cell lines.
  
  
  RESULTS
  Fez1/Lzts1 protein was barely detectable in all of the gastric cancer cell lines tested and was absent or significantly reduced in 39 of the 88 (44.3%) gastric carcinomas analyzed by immunohistochemistry, with a significant correlation (P < 0.001) to diffuse histotype. DNA allelotyping analysis 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 Fez1/Lzts1. Hypermethylation of the CpG island flanking the Fez1/Lzts1 promoter was evident in six of the eight cell lines examined as well as in the normal control.
  
  
  CONCLUSIONS
  Our findings support FEZ1/LZTS1 as a candidate tumor suppressor gene at 8p in a subtype of gastric cancer and suggest that its inactivation is attributable to several factors including genomic deletion and methylation.
authors: Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: A
authors: A
authors: Vecchione
authors: H
authors: H
authors: Ishii
authors: Y H
authors: YH
authors: Shiao
authors: F
authors: F
authors: Trapasso
authors: M
authors: M
authors: Rugge
authors: J F
authors: JF
authors: Tamburrino
authors: Y
authors: Y
authors: Murakumo
authors: H
authors: H
authors: Alder
authors: C M
authors: CM
authors: Croce
authors: R
authors: R
authors: Baffa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D001483:Base Sequence; D015139:Blotting, Southern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002898:Chromosomes, Human, Pair 8; D018899:CpG Islands; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D017353:Gene Deletion; D015723:Gene Library; D016147:Genes, Tumor Suppressor; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C528597:FEZ1 protein, human; C118711:LZTS1 protein, human; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA