Matrix metalloproteinase 3 polymorphism: a predictive factor of response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma.
OBJECTIVE
Treatment of head and neck cancer often associates different therapeutic modalities, including surgery, radiotherapy, and chemotherapy. In an attempt to optimize therapeutics, the identification of molecular markers linked to response to chemotherapy remains important. Recently, the involvement of metalloproteinases in resistance to chemotherapy was suggested through their interaction with the Fas/Fas ligand pathway. Indeed metalloproteinases enhance Fas ligand shedding modulating chemotherapy efficiency. On the basis of these findings, we tested the existence of a correlation between response to chemotherapy and four metalloproteinase polymorphisms in a prospective series of 148 head and neck cancer patients.


METHODS
Patients were genotyped using automated fragment analysis and 5'-nuclease allelic discrimination assay. Response to chemotherapy was clinically assessed without knowledge of the genotype status.


RESULTS
A significant relation between the metalloproteinase type 3 (MMP3) -1612insA polymorphism and response to chemotherapy was identified. Indeed, patients with the 6A/6A genotype responded more frequently (86%) to treatment as compared with patients with the 5A/6A (65%) or 5A/5A (55%) genotypes (P = 0.04). A multivariate analysis, including tumor stage, gender, TP53 mutations, and MMP3 polymorphism, showed that the 6A/6A genotype was an independent factor of response to 5-fluorouracil-cisplatin chemotherapy in head and neck cancer patients with an odds ratio of 6.7 as compared with the 5A/5A genotype.


CONCLUSIONS
This work showed that genotyping the MMP3 gene enhancer polymorphism -1612insA could help predict chemosensitivity in head and neck cancer patients.
Blons
Hélène
H
Inserm 490 Laboratoire de Toxicologie Moléculaire, Université René Descartes ParisV, Paris.
Gad
Sophie
S
Zinzindohoué
Franck
F
Manière
Isabelle
I
Beauregard
Janie
J
Tregouet
David
D
Brasnu
Daniel
D
Beaune
Philippe
P
Laccourreye
Ollivier
O
Laurent-Puig
Pierre
P
D000368:Aged; D000483:Alleles; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000627:therapeutic use; D053222:Fas Ligand Protein; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D016158:Genes, p53; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011379:Prognosis; D011446:Prospective Studies; D012737:Sex Factors; D016896:Treatment Outcome; D019014:fas Receptor / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020781:Matrix Metalloproteinase 1; D002945:Cisplatin; D005472:Fluorouracil