Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival

Nat Commun. 2014 Dec 17:5:5835. doi: 10.1038/ncomms6835.

Abstract

The arachidonic acid metabolism (AAM) pathway promotes tumour progression. Chemical inhibitors of AAM pathway prolong post-treatment survival of cancer patients. Here we test whether non-synonymous somatic mutations in genes of this pathway, acting as natural inhibitors, increase post-treatment survival. We identify loss-of-function somatic mutations in 15 (18%) of 84 treatment-naïve oral cancer patients by whole-exome sequencing, which we map to genes of AAM pathway. Patients (n = 53) who survived ≥ 12 months after surgery without recurrence have significantly (P = 0.007) higher proportion (26% versus 3%) of mutations than those who did not (n = 31). Patients with mutations have a significantly (P = 0.003) longer median disease-free survival (24 months) than those without (13 months). Compared with the presence of a mutation, absence of any mutation increases the hazard ratio for death (11.3) significantly (P = 0.018). The inferences are strengthened when we pool our data with The Cancer Genome Atlas (TCGA) data. In patients with AAM pathway mutations, some downstream pathways, such as the PI3K-Akt pathway, are downregulated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonic Acids / genetics
  • Arachidonic Acids / metabolism*
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / surgery
  • Cytochrome P-450 CYP2C19 / genetics
  • Cytochrome P-450 CYP2C19 / metabolism
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytochrome P450 Family 2
  • Gene Expression*
  • Glutathione Peroxidase
  • Group III Phospholipases A2 / genetics
  • Group III Phospholipases A2 / metabolism
  • Group IV Phospholipases A2 / genetics
  • Group IV Phospholipases A2 / metabolism
  • Group VI Phospholipases A2 / genetics
  • Group VI Phospholipases A2 / metabolism
  • Humans
  • Metabolic Networks and Pathways / genetics*
  • Mouth Neoplasms / genetics*
  • Mouth Neoplasms / mortality
  • Mouth Neoplasms / pathology
  • Mouth Neoplasms / surgery
  • Mutation*
  • Peroxidases / genetics
  • Peroxidases / metabolism
  • Proportional Hazards Models
  • Survival Analysis
  • Thromboxane-A Synthase / genetics
  • Thromboxane-A Synthase / metabolism
  • Treatment Outcome
  • gamma-Glutamyltransferase / genetics
  • gamma-Glutamyltransferase / metabolism

Substances

  • Arachidonic Acids
  • Cytochrome P-450 Enzyme System
  • Peroxidases
  • GPX7 protein, human
  • Glutathione Peroxidase
  • CYP2C19 protein, human
  • CYP2U1 protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P450 Family 2
  • gamma-Glutamyltransferase
  • Group III Phospholipases A2
  • Group IV Phospholipases A2
  • Group VI Phospholipases A2
  • PLA2G3 protein, human
  • PLA2G4E protein, human
  • PLA2G4F protein, human
  • PLA2G6 protein, human
  • PTGIS protein, human
  • Thromboxane-A Synthase