title: Chromosomal instability rather than p53 mutation is associated with response to neoadjuvant cisplatin-based chemotherapy in gastric carcinoma.
abstract: OBJECTIVE
  The objective of the study was to evaluate microsatellite alterations [microsatellite instability (MSI) and loss of heterozygosity (LOH)] and mutation in the p53 gene in relation to response and patient survival to a cisplatin-based neoadjuvant chemotherapy in gastric cancer.
  
  
  METHODS
  Fifty-three pretherapeutic gastric carcinoma biopsies were analyzed with 11 microsatellite markers. The entire coding region of the p53 gene (exons 2-11) was analyzed for mutations by denaturing high-pressure liquid chromatography and sequencing. p53 protein expression was evaluated by immunohistochemistry. Patients were treated with a cisplatin-based, neoadjuvant chemotherapy regimen. Therapy response was evaluated by computed tomography scan, endoscopy, and endoluminal ultrasound. The median follow-up of the patients was 45.6 months.
  
  
  RESULTS
  p53 mutations were identified in 19 of the 53 (36%) analyzed tumors. No significant association with response or survival was found for p53 mutation or for p53 protein expression. MSI (either high-grade MSI or low-grade MSI) did not show a correlation with response. With respect to LOH, LOH at chromosome 17p13 showed a significant association with therapy response (P = 0.022) but did not reach statistical significance in terms of patient survival. The global LOH rate, expressed as fractional allelic loss (FAL), was assessed, and tumors were classified into tumors with a high (>0.5), medium (>0.25-0.5), and low (0-0.25) FAL value. A statistically significant association of FAL with therapy response was found (P = 0.003), with a high FAL being related to therapy response. The sensitivity, specificity, positive predictive value, and negative predictive value for FAL > 0.5 were 45%, 93%, 82%, and 72%, respectively.
  
  
  CONCLUSIONS
  A high level of chromosomal instability (high FAL value) defines a subset of patients who are more likely to benefit from cisplatin-based neoadjuvant chemotherapy. p53 mutation status is not significantly associated with therapy response and is not a useful marker for response prediction.
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675 Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Ott
authors.forename: Holger
authors.initials: H
authors.lastname: Vogelsang
authors.forename: James
authors.initials: J
authors.lastname: Mueller
authors.forename: Karen
authors.initials: K
authors.lastname: Becker
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Fink
authors.forename: Jörg Rüdiger
authors.initials: JR
authors.lastname: Siewert
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Gisela
authors.initials: G
authors.lastname: Keller
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D017024:Chemotherapy, Adjuvant; D043171:Chromosomal Instability; D002945:Cisplatin / Q000627:therapeutic use; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D016159:Tumor Suppressor Protein p53; D002945:Cisplatin