title: Loss of heterozygosity at thymidylate synthase locus in Barrett's metaplasia, dysplasia, and carcinoma sequences.
abstract: BACKGROUND
  Thymidylate synthase (TS) is known to have a unique 28 bp tandemly repeated sequence in the promoter region, and the majorities of subjects have a heterozygous double repeat/triple repeat genotype in their non-cancerous tissue. Loss of heterozygosity (LOH) at the TS locus is known to occur in cancer patients, but there is no evidence that it is present in precancerous tissue. The aim of this study was to analyze the frequency and timing of LOH at the TS locus in Barrett-associated adenocarcinoma (BA) and its precursory lesions, such as intestinal metaplasia (IM) and dysplasia.
  
  
  METHODS
  One hundred twenty-three samples (including 37 with gastroesophageal reflux disease (GERD), 29 with IM, 13 with dysplasia, and 44 with BA) were obtained from 100 patients. Biopsies were obtained from the lower esophageal mucosa/IM/dysplasia/BA, when available. Normal squamous tissue from the upper esophagus was taken as a control. All tissues were analyzed for the TS genotype and TS mRNA expression using the real-time reverse-transcription polymerase chain reaction (RT-PCR) method after laser-capture microdissection.
  
  
  RESULTS
  Among the patients with informative heterozygous genotype in their control samples, no sample with LOH at the TS locus was observed in the lower esophageal mucosa in GERD patients (0/22 samples). However, 6 out of 21 samples (28.6%) had LOH in IM, 2 of 7 (28.6%) in dysplasia, and 10 of 25 (40.0%) in BA. No significant difference in TS mRNA expression levels was observed between TS genotypes.
  
  
  CONCLUSIONS
  Our results demonstrate that LOH is a relatively frequent and early event in the IM-BA sequence.
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA. kuramochi@hosp.net
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kuramochi
authors.forename: Kazumi
authors.initials: K
authors.lastname: Uchida
authors.forename: Jeffery H
authors.initials: JH
authors.lastname: Peters
authors.forename: Daisuke
authors.initials: D
authors.lastname: Shimizu
authors.forename: Daniel
authors.initials: D
authors.lastname: Vallbohmer
authors.forename: Sylke
authors.initials: S
authors.lastname: Schneider
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Danenberg
authors.forename: Peter V
authors.initials: PV
authors.lastname: Danenberg
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D004947:Esophagus / Q000473:pathology; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D008679:Metaplasia / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009385:Neoplastic Processes; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D013940:Thymidylate Synthase