Isocitrate Dehydrogenase 1 (IDH1) Mutation in Breast Adenocarcinoma Is Associated With Elevated Levels of Serum and Urine 2-Hydroxyglutarate

Abstract

Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR1) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR1 breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme. The Oncologist 2014; 19:602-607 Implications for Practice: Isocitrate dehydrogenase (IDH) mutations have been identified in various hematologic and solid-tumor malignancies. To date, there are no published reports of these mutations in breast cancer. With this article, we describe a case of hormone receptor-positive adenocarcinoma of the breast with an IDH1 (p.R132L) mutation. The impacted patient had markedly elevated levels of serum and urine 2-hydroxyglutarate, an oncometabolite that accumulates as a result of the neomorphic activity of the altered IDH enzyme. IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma, and these findings may carry future therapeutic implications, given the emergence of targeted therapies against the altered IDH protein.

IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity

“…High 2HG concentrations disrupt TET2 catalytic function and prevent hydroxylation of 5-methylcytosine, resulting in attenuated TET2 -dependent demethylation of DNA (30,45). Akin to IDH -mutant glioma, AML and common forms of breast carcinoma harboring IDH1 mutations (33,34,46), we found high concentrations of intratumoral 2HG in the IDH2 -mutant SPCRP successfully tested; the use of archival material makes this analysis challenging as formalin fixation and paraffin embedding may lead to oncometabolite loss (21). In addition, we observed global DNA hypermethylation and H3K27 trimethylation in IDH2 / TET2 –mutant SPCRPs as compared to IDH2 wild-type IDCs, consistent with those reported in IDH1 / IDH2 -mutant cancers (26,30,31,35).…”

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

“…In gliomas and myeloid leukemia, D-2HG accumulates in tumors because of IDH mutations (9,10). However, these mutations are rare in breast cancer (39). Instead, 2HG accumulates in breast tumors in association with MYC signaling (7).…”

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma

“…Serum or urine levels of 2-HG have been studied as biomarkers of disease activity in various IDH-mutant malignancies [23,26]. Studies in acute myeloid leukemia have detected elevated circulating 2-HG levels during treatment [23].…”