Chromosomal instability rather than p53 mutation is associated with response to neoadjuvant cisplatin-based chemotherapy in gastric carcinoma.
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.
Ott
Katja
K
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, D-81675 Munich, Germany.
Vogelsang
Holger
H
Mueller
James
J
Becker
Karen
K
Müller
Martina
M
Fink
Ulrich
U
Siewert
Jörg Rüdiger
JR
Höfler
Heinz
H
Keller
Gisela
G
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
D016159:Tumor Suppressor Protein p53; D002945:Cisplatin