IDH mutation status in prostate cancer

Abstract

In a recent Oncogene review, Yen et al. summarized the important role of somatic mutations in the cytoplasmic and mitochondrial forms of isocitrate dehydrogenase (IDH1 and IDH2, respectively) in cancer. These gliomaand acute myeloid leukemia-associated mutations occur at IDH1 codon 132 (that is, R132) or in IDH2, at codon 172 or 140 (that is, R172, R140). Although cancer-associated IDH1/2 mutations impair the wild-type IDH activity of the enzymes, they activate a novel enzymatic function in converting aketoglutarate to 2-hydroxyglutarate, which leads to DNA hypermethylation and increased angiogenesis through stabilization of hypoxia-inducible transcription factor-1a. Yen et al. highlighted the value of documenting mutant IDH1 and IDH2 enzymes as targets for individualized and novel cancer therapies. We have determined IDH1/2 mutations in localized prostate cancer (PCa), which has significant heterogeneity in genomic stability, tumor metabolism and clinical outcome. Mutational and array comparative genomic hybridization analyses for R132, R172 or R140 mutations as well as IDH1/2 allelic copy number were conducted in 158 PCa DNA samples following IRB consent, as previously described. IDH1 and IDH2 mutations were determined using a Sequenom MassARRAY platform and confirmed by direct Sanger sequencing. Our analysis revealed an IDH1 R132C mutation in one patient (T1cN0M0, Gleason score 6; prostate-specific antigen 4.8 ng/ml) and an IDH1 R132H mutation in a second patient (T2aN0M0, Gleason score 7; prostate-specific antigen 33 ng/ml). No IDH2 mutations were detected (Table 1). Our study population also was assessed for allelic loss at 10q (PTEN), 8P (NKX3.1), 17p (p53) and gain at 8q21 (c-MYC). However, these genetic alterations neither uniquely associate with IDH mutation nor with allelic gain/loss of IDH1/2 (found in four other patients; see Supplementary Table 1). Mutation or allelic loss of IDH1/2 is therefore rare in localized PCa, based on our large series and previous data (Table 1). However, in the era of personalized medicine, the 2% of patients with mutated IDH1 PCa could be considered for future mutant IDH-targeted therapy and possibly prevent the need for local therapies with side effects (for example, radiotherapy or surgery). Given the role of hypoxia and altered metabolism in PCa heterogeneity and prognosis, further research is warranted on mutations that may alter PCa hypoxia and/or metabolism, which could lead to novel and personalized therapy in subgroups of localized PCa patients.