A GTP cyclohydrolase 1 genetic variant delays cancer pain

Pain is a major symptom in 70% of patients with advanced cancer. We analyzed data of 251 cancer patients (142 men and 109 women aged 29-89 years, Karnofsky status 10-90, 65.7 ± 13.9) for association of a reduced-function haplotype in the GTP cyclohydrolase 1 (GCH1) gene with cancer pain therapy. The interval between cancer diagnosis and opioid therapy initiation was significantly (p = 0.002) longer in homozygous carriers of these genetic variants (78 ± 65.2 months) than in heterozygous (37 ± 46.5 months) and non-carriers (30.4 ± 43.8 months). Thus, reduced GCH1 upregulation, here conferred by non-coding and non-splice site GCH1 variants known to lead to decreased tetrahydrobiopterin expression, delays the need for opioid therapy in cancer. This suggests the future possibility of using partial GCH1 blockade or BH4 inhibition as a prophylactic to prevent or delay the development of cancer pain.