Loss of heterozygosity and microsatellite instability as predictive markers for neoadjuvant treatment in gastric carcinoma.
We analyzed a group of gastric carcinomas treated with a cisplatin-based neoadjuvant chemotherapy regimen for microsatellite instability (MSI) and loss of heterozygosity (LOH) to determine whether there is any relation between microsatellite alterations and therapy response. Pretherapeutic endoscopic biopsies of 37 patients were studied at 11 microsatellite loci. Thirteen (35%) had a complete or partial clinical response (responders), and 24 (65%) had only a minor or no response (nonresponders). High-grade MSI was found in two tumors, both nonresponders, whereas low-grade MSI was found in five biopsies, including three non-responders and two responders. Regarding LOH, the most obvious differences between the groups were observed on chromosome 17p13, the location of the p53 gene, with 7 of 12 (58%) and 3 of 20 (15%) of the informative tumors exhibiting LOH in responders and nonresponders, respectively (P = 0.018). A statistically significant difference was also observed in the fractional allelic loss (FAL) ratio of the groups. Among the 13 responding patients, 7 (54%) tumors exhibited high FAL (>0.5-0.75), 2 (15%) showed medium FAL (>0.25-0.5), and 4 (31%) demonstrated low FAL values (0-0.25), whereas among the 22 nonresponding patients, 2 (9%) tumors showed high FAL, 5 (23%) showed medium FAL, and 15 (68%) showed low FAL (P = 0.020). These data suggest that LOH at chromosome 17p13 is associated with a good clinical response to cisplatin-based chemotherapy, suggesting that altered p53 function might render cells more sensitive to therapy. Furthermore, the association of FAL with therapy response indicates that gastric carcinomas with a high level of chromosomal alteration may be more sensitive to this type of chemotherapy.
Grundei
T
T
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. grundei@nt1.chir.med.tu-muechen.de
Vogelsang
H
H
Ott
K
K
Mueller
J
J
Scholz
M
M
Becker
K
K
Fink
U
U
Siewert
J R
JR
Höfler
H
H
Keller
G
G
D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002277:Carcinoma / Q000235:genetics* / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D002886:Chromosomes, Human, Pair 17; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000235:genetics* / Q000628:therapy*; D016896:Treatment Outcome
D000970:Antineoplastic Agents