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

• Published in: British journal of cancer 2020-09, Vol.123 (5), p.772-784
• Main Authors: Morvan, Valérie Le, Richard, Élodie, Cadars, Maud, Fessart, Delphine, Broca-Brisson, Léa, Auzanneau, Céline, Pasquies, Alban, Modesto, Anouchka, Lusque, Amélie, Mathoulin-Pélissier, Simone, Lansiaux, Amélie, Robert, Jacques
• Format: Article
• Language: English
• Subjects: 631/208; 631/67; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor agents; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cell Growth Processes - physiology; Cell Line, Tumor; Cell migration; Cell Movement - physiology; Cell proliferation; Cetuximab - administration & dosage; Chemotherapy; Cytochrome; Cytochrome P-450 CYP1B1 - genetics; Cytochrome P450; DNA damage; DNA Methylation; Drug efficacy; Drug Resistance; Epidemiology; Female; Gene expression; Gene polymorphism; Growth rate; Head; Head & neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Heterografts; Humans; Invasiveness; Male; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Medicine; Neck; Neoplasm Invasiveness; Neoplastic Stem Cells - enzymology; Neoplastic Stem Cells - pathology; Oncology; Polymorphism; Promoter Regions, Genetic; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - enzymology; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - pathology; Stem cells; Transcriptomes; Tumor cell lines; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0932-5

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.