title: Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival.
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.
authors.affiliation: National Institute of Biomedical Genomics, Netaji Subhas Sanatorium (2nd Floor), Kalyani 741251, India.
authors.forename: Nidhan K
authors.initials: NK
authors.lastname: Biswas
authors.affiliation: National Institute of Biomedical Genomics, Netaji Subhas Sanatorium (2nd Floor), Kalyani 741251, India.
authors.forename: Subrata
authors.initials: S
authors.lastname: Das
authors.affiliation: National Institute of Biomedical Genomics, Netaji Subhas Sanatorium (2nd Floor), Kalyani 741251, India.
authors.forename: Arindam
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sarin
authors.affiliation: National Institute of Biomedical Genomics, Netaji Subhas Sanatorium (2nd Floor), Kalyani 741251, India.
authors.forename: Partha P
authors.initials: PP
authors.lastname: Majumder
mesh_terms: D001095:Arachidonic Acids / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D015870:Gene Expression; D005979:Glutathione Peroxidase; D054520:Group III Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D009062:Mouth Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D009154:Mutation; D010544:Peroxidases / Q000235:genetics / Q000378:metabolism; D016016:Proportional Hazards Models; D016019:Survival Analysis; D013930:Thromboxane-A Synthase / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D003577:Cytochrome P-450 Enzyme System; D010544:Peroxidases; C558641:GPX7 protein, human; D005979:Glutathione Peroxidase; C045793:CYP2C19 protein, human; C484320:CYP2U1 protein, human; D065731:Cytochrome P-450 CYP2C19; D000072467:Cytochrome P450 Family 2; D005723:gamma-Glutamyltransferase; D054520:Group III Phospholipases A2; D054513:Group IV Phospholipases A2; D054522:Group VI Phospholipases A2; C484163:PLA2G3 protein, human; C516418:PLA2G4E protein, human; C516419:PLA2G4F protein, human; C516475:PLA2G6 protein, human; C472456:PTGIS protein, human; D013930:Thromboxane-A Synthase