Cytochrome P450 1B1 polymorphism drives cancer cell stemness and patient outcome in head-and-neck carcinoma.

BACKGROUND: Cytochrome P450 1B1 (CYP1B1) is mostly expressed in tumours and displays unusual properties. Its two polymorphic forms were differently associated with anticancer drug sensitivity. We decipher here the role of this polymorphism in anticancer drug efficacy in vitro, in vivo and in the clinical setting. METHODS: From head-and-neck squamous cell carcinoma cell lines not expressing CYP1B1, we generated isogenic derivatives expressing the two forms. Proliferation, invasiveness, stem cell characteristics, sensitivity to anticancer agents and transcriptome were analysed. Tumour growth and chemosensitivity were studied in vivo. A prospective clinical trial on 121 patients with advanced head-and-neck cancers was conducted, and a validation-retrospective study was conducted. RESULTS: Cell lines expressing the variant form displayed high rates of in vitro proliferation and invasiveness, stemness features and resistance to DNA-damaging agents. In vivo, tumours expressing the variant CYP1B1 had higher growth rates and were markedly drug-resistant. In the clinical study, overall survival was significantly associated with the genotypes, wild-type patients presenting a longer median survival (13.5 months) than the variant patients (6.3 months) (p = 0.0166). CONCLUSIONS: This frequent CYP1B1 polymorphism is crucial for cancer cell proliferation, migration, resistance to chemotherapy and stemness properties, and strongly influences head-and-neck cancer patients' survival.

Predicting drug response and toxicity based on gene polymorphisms.

The sequencing of the human genome has allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphims (SNP), which may play an important role in the expression level and activity of the corresponding proteins. When these polymorphisms occur at the level of drug metabolising enzymes or transporters, the disposition of the drug may be altered and, consequently, its efficacy may be compromised or its toxicity enhanced. Polymorphisms can also occur at the level of proteins directly involved in drug action, either when the protein is the target of the drug or when the protein is involved in the repair of drug-induced lesions. There again, these polymorphisms may lead to alterations in drug efficacy and/or toxicity. The identification of functional polymorphisms in patients undergoing chemotherapy may help the clinician prescribe the optimal drug combination or schedule and predict with more accuracy the response to these prescriptions. We have recorded in this review the polymorphisms that have been identified up till now in genes involved in anticancer drug activity. Some of them appear especially important in predicting drug toxicity and should be determined in routine before drug administration; this is the case of the most common variations of thiopurine methyltransferase for 6-mercaptopurine and of dihydropyrimidine dehydrogenase for fluorouracil. Other appear determinant for drug response, such as the common SNPs found in glutathione S-transferase P1 or xereoderma pigmentosum group D enzyme for the activity of oxaliplatin. However, confusion factors may exist between the role of gene polymorphisms in cancer risk or overall prognosis and their role in drug response.