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 (HR+) 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 HR+ 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.

Keywords: 2-Hydroxyglutarate; Breast adenocarcinoma; Isocitrate dehydrogenase 1; Targeted therapy.

Figure 1.

Identification of an IDH1 p.R132L mutation in tumor tissue from a breast cancer patient. A 61-year-old female patient diagnosed with estrogen receptor-positive, progesterone receptor-positive, human epidermal growth factor receptor 2-negative invasive ductal carcinoma underwent mutational profiling. An IDH1 c.395G>T (p.R132L) mutation (green peak) was identified in tissue obtained by lumpectomy from the left breast, central duct, and the sentinel lymph node (upper panels). Tissue from a subsequent left-sided mastectomy and lymph node dissection was evaluated and the same IDH1 mutation was identified in malignant breast tissue (LB) and the left axillary lymph node (middle panels). Conversely, no IDH1 p.R132 mutation was found in an uninvolved lymph node, where no malignancy was found during pathological review. Metastatic lesions obtained from a later surgery were also identified to harbor the IDH1 p.R132L mutation from two lymph nodes (LN1 and LN2) (lower panels). Abbreviations: CD, central duct; IDH1, isocitrate dehydrogenase 1 gene; LALN, left axillary lymph node; LB, left breast; LN, lymph node; NM, no malignancy; SLN, sentinel lymph node.

Figure 2.

2-HG measurements in samples from patients with a wild-type IDH1 (n = 6) versus the patient harboring the IDH1 p.R132L mutation in serum (A) and urine (B). Each point represents an individual patient sample, with blue dots depicting IDH1-wild-type samples and the red dots depicting IDH1-mutant samples. The left column in each figure represents the wild-type samples and the right column represents the mutant sample. Horizontal bars indicate the median, and vertical lines indicate the lower and upper quartiles. All figures describe a statistically significant difference in 2-HG levels between the IDH1-mutant sample relative to the wild-type samples (p < .05). Abbreviations: 2-HG, 2-hydroxyglutarate; IDH1, isocitrate dehydrogenase 1 gene; WT, wild-type.