Prognostic significance of MMP-1 and MMP-3 functional promoter polymorphisms in colorectal cancer.
OBJECTIVE
Matrix metalloproteinase (MMP) belongs to a large group of proteases capable of breaking essentially all components of the extracellular matrix. They are implicated in all steps of tumorogenesis, cancer invasion, and metastasis. Among them, metalloproteinase type 1 (MMP-1) is implicated in tumor invasion and metastasis in different types of cancers including colorectal cancer in which its expression was correlated with poor prognosis. A polymorphism in the promoter region of the MMP-1 gene leads to a variation of its level of transcription.


METHODS
MMP-1 -1607ins/delG and MMP-3 - 1612 ins/delA promoter polymorphisms were genotyped by multiplex PCR from 201 colorectal cancer patients. The median follow-up of patients was 30 months. The MMP genotypes were correlated to clinical outcome.


RESULTS
Patients with the -1607insG/-1607insG MMP-1 genotype had significantly worse specific survival than the others in the whole series (P < 0.04), in stage I to III patients (P < 0.001), and in patients stage I and II (P < 0.01). In multivariate analysis, MMP-1-1607insG allele showed to be an independent poor prognostic factor after adjustment on stage, age, and the use of adjuvant chemotherapy. MMP-3 polymorphism was not associated with survival.


CONCLUSIONS
In the subgroups of nondistant metatastic patients (stages I and II, and stages I-III), an inverse relation between the number of MMP-1-1607insG allele and survival was observed suggesting a gene dosage effect. Our results are consistent with the importance of MMP-1-1607ins/delG functional polymorphism in regulating transcription level and with the relationship between MMP-1 expression and cancer invasion, metastasis, and prognosis.
Zinzindohoué
Franck
F
INSERM U490, Laboratoire de toxicologie Moléculaire, 45 rue des Saintes Pères, 75006 Paris, France.
Lecomte
Thierry
T
Ferraz
Jean-Marc
JM
Houllier
Anne-Marie
AM
Cugnenc
Paul-Henri
PH
Berger
Anne
A
Blons
Hélène
H
Laurent-Puig
Pierre
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D005260:Female; D005838:Genotype; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1