Isocitrate dehydrogenase 1 mutations in melanoma frequently co-occur with NRAS mutations

Aims Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that converts isocitrate to alpha-ketoglutarate. IDH1 mutations are associated with the accumulation of the oncometabolite D-2-hydroxyglutarate, which acts as an epigenetic modifier, and the development of multiple malignancies. Methods and results From May 2013 to June 2017, 252 melanoma samples from 214 patients with advanced or distant metastatic disease were tested for somatic mutations with the 50-gene AmpliSeq version 2 Cancer Hotspot Panel. Two hundred and twenty-six samples were sequenced successfully from 206 patients with 26 samples being characterised as quantity not sufficient. Melanomas from 10 separate patients (4.9%) were positive for IDH1 R132C (nine) or R132S (one). In six cases, the tumours also had a co-existing NRAS mutation (p.Q61R, Q61L and Q61K in two patients each) (P = 0.0044), whereas three patients had BRAF non-V600E mutations (V600K, V600G and V600R). Two cases had a TP53 variant, two cases an ATM variant, one a CDKN2A variant and one had an APC variant. The patients' ages ranged from 45 to 82 years (mean = 65.3, median = 65 years) and three of 10 patients were female (M:F ratio = 2:3). Three patients were stage 3 and seven were stage 4. Two are deceased, five are alive with stable disease (four on pembrolizumab) and three have no evidence of disease. Conclusion IDH mutations may define a unique subset of melanoma patients who are eligible for IDH1 targeted therapies or combined therapies, such as MEK inhibitors when there is co-existing NRAS mutations, or immunotherapy.