Common genetic mutations in HNSCC and their implication for tumor cell metabolism
| Gene | Frequency (%)45 | Implications for metabolism |
|---|---|---|
| Loss of function mutations/deletions | ||
| TP53 | 50-80 | Loss of p53 leads to nuclear and mitochondrial DNA instability, increased oxidative stress, decrease of OXPHOS and up-regulation of glycolysis (reviewed in46,47) |
| NOTCH1 | 14-15 | Hypoactive Notch diminishes p53 levels and attenuates mitochondrial function, causing a switch to glycolysis and dependence on glucose48 |
| PTEN | 7 | PTEN counteracts glycolysis by reversing the PI3K-mediated conversion of phosphatidylinositol1,4-biphosphate (PIP2) to phosphatidylinositol1,4,5-triphosphate (PIP3) that is required to activate Akt-mTOR signaling. Loss of PTEN therefore increases Akt activation. PTEN also counteracts glutaminolysis by reducing glutaminase levels through a PI3K-independent pathway49 |
| Gain of function mutations/amplifications | ||
| PIK3CA | 6-20 | PIK3CA encodes p110α, an isoform of the 110-kDa catalytic subunit of the class 1A phosphatidylinositol-3-kinase (PI3K). The PI3K-Akt-mTOR pathway is one of the most frequently hyperactivated signaling cascades in tumor cells. Enhanced Akt signaling induces a Warburg phenotype and increases the coupling of glycolysis to the mitochondrial citric acid cycle which yields intermediates for biosynthetic pathways and NADH as the primary electron donor for OXPHOS (reviewed in50) |
| HRAS | 4-5 | HRAS encodes the small GTPase H-Ras, a member of the Ras superfamily of enzymes that become active when bound to GTP. Besides other pathways important for cell survival and proliferation, Ras-GTP directly acivates PI3K p110. Oncogenic H-Ras activation diminishes mitochondrial respiration, rendering transformed cells depend on glucose to fuel glycolysis51 |