Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer.
Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7(-181A>G). In addition, the genotype distribution of MMP-7(-181A>G) was associated with Helicobacter pylori status (chi(2) 7.8, P=0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2(303C>T) correlated significantly with the WHO classification (chi(2) 5.9, P=0.03) and also strongly with tumour-related survival (log rank 11.74, P=0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2(-1306C>T) polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7(-181A>G) and TIMP-2(303C>T) polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7(-181A>G) and TIMP-2(303C>T), may be helpful in identifying gastric cancer patients with a poor clinical outcome.
Kubben
F J G M
FJ
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
Sier
C F M
CF
Meijer
M J W
MJ
van den Berg
M
M
van der Reijden
J J
JJ
Griffioen
G
G
van de Velde
C J H
CJ
Lamers
C B H W
CB
Verspaget
H W
HW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*; D015996:Survival Rate; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics*
D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases