Microsatellite analysis and response to chemotherapy in head-and-neck squamous-cell carcinoma.
Molecular studies have revealed that microsatellite instability and loss of heterozygosity occurred in head-and-neck cancer, suggesting the involvement both of suppressor and of mutator pathways in head-and-neck carcinogenesis. There is evidence for relations between tumor phenotype and clinical parameters. Indeed, replication-error phenotype, characterized by microsatellite instability, was associated with decreased sensitivity to chemotherapeutic agents in cell lines. Loss of heterozygosity is a frequent mechanism of inactivation of tumor-suppressor genes, which might be implicated in resistance to chemotherapy. In head-and-neck cancer, chemosensitivity is inconstant, and no marker is available to predict response to treatment. In order to evaluate the role of tumor phenotype on resistance to chemotherapy, we analyzed 56 primary head-and-neck squamous-cell carcinomas collected at time of diagnosis and a sub-group of 23 resistant tumors collected after chemotherapy at 22 microsatellite loci. At time of diagnosis, only one tumor showed MSI-H phenotype. Loss of heterozygosity (LOH) was observed in 75% of tumors, indicating the dominant role of the suppressor in comparison with the mutator pathway in HNSCC carcinogenesis. No change in microsatellite patterns was observed after treatment, suggesting that chemotherapy did not select mismatch-repair-deficient clones. Univariate analyses showed that LOH at 9p or 17p was significantly associated with drug resistance. In a multivariate analysis, only LOH at 17p remains predictive of low response to chemotherapy, with a relative risk of 3.7 and 95% CI of 1.1-13, indicating that p53 alterations could play a role in chemotherapy resistance in HNSCC. Int. J. Cancer (Pred. Oncol.) 84:410-415, 1999.
U490 INSERM Laboratoire de Toxicologie Moléculaire, Paris, France.
H
H
Blons
A
A
Cabelguenne
F
F
Carnot
O
O
Laccourreye
I
I
de Waziers
R
R
Hamelin
D
D
Brasnu
P
P
Beaune
P
P
Laurent-Puig
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016009:Chi-Square Distribution; D002886:Chromosomes, Human, Pair 17; D002887:Chromosomes, Human, Pair 18; D002893:Chromosomes, Human, Pair 3; D002898:Chromosomes, Human, Pair 8; D002899:Chromosomes, Human, Pair 9; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012044:Regression Analysis
D002945:Cisplatin; D005472:Fluorouracil