Low level of isocitrate dehydrogenase 1 predicts unfavorable postoperative outcomes in patients with clear cell renal cell carcinoma

Renal cell carcinoma (RCC) is the most common type of malignant tumor in kidney, which represents the sixth most common cancer in men and the tenth most common cancer in women [1]. Clear cell RCC (ccRCC) is the prominent histological subtype of RCC, which accounts for about 80% to 90% of all RCC patients [2]. However, despite nephrectomy may cure the majority of localized RCC, about one third of the patients undergo local recurrence or distant metastasis after nephrectomy [3]. Currently, several clinical or pathological outcome prediction systems have already been established to evaluate the outcomes of patients with RCC, such as the University of California Los Angeles integrated staging system (UISS), the Mayo clinic stage, size, grade, and necrosis score (SSIGN), and the TNM stage, Fuhrman grade, Eastern Cooperative Oncology Group performance status (ECOG PS) [4‐6]. However, due to the heterogeneity of molecular phenotype, there is a long way to go to predict the clinical outcomes of ccRCC [7, 8]. Therefore, new prognosis prediction systems with high accuracy are imperative needed for patients with ccRCC.

Altered cellular metabolism in cancers was observed for many years [9]. Despite the presence of enough oxygen, cancer cells still show high levels of glycolysis, which means the altered cell metabolic regulation plays an important role in tumorigenesis [10]. Isocitrate dehydrogenases (IDHs) are comprised of three members: IDH1, IDH2 and IDH3 [11]. IDH1 mainly catalyzes the conversion of isocitrate to alpha-ketoglutarate (aKG), and provides sufficient NADPH and regulates the biosynthesis of cholesterol and fatty acid [12]. Recently, many studies showed that IDH1 is mutated in various human cancers, especially in low-grade glioma [13]. The most common mutation site of IDH1 is the R132H, which acquires the ability to catalyze the reduction of a-KG to 2-hydroxyglutarate (2-HG) [14]. Moreover, several studies indicated that the R132H mutation of IDH1 correlates with a favorable prognosis for patients with glioma and gastrointestinal cancer [15, 16]. Nevertheless, little research was conducted to investigate the relationship between wide-type IDH1 and tumors. Sun and colleagues reported that IDH1 was significantly higher in patients with non-small cell lung cancer than in healthy controls [17]. However, the exact role of IDH1 in ccRCC, especially patients with high risk, is remains unknown.

The aim of this study was to reveal the clinical role of IDH1 in ccRCC patients. Moreover, two prognostic nomograms integrating IDH1 expression and clinical factors were established to predict the outcomes and may guide clinical decisions making for ccRCC patients.

IDH1, a NADP-dependent enzyme which involves in the control of oxidative cellular damage, was identified as a tumor suppressor since its inactivation plays a vital role in tumorigenesis [26, 27]. Although IDH1 have consistently been reported take part in the genesis of many cancers, the correlation between IDH1 expression and ccRCC outcomes remains unclear. In this study, we detected IDH1 was mainly expressed in the cytoplasm of ccRCC tumor cells, and low expression level of IDH1 in tumor correlated with an adverse outcomes of ccRCC, especially in patients with high SSIGN scores. Besides, IDH1 expression level was a risk factor of OS and RFS for ccRCC patients. Furthermore, by integrating with several factors from multivariate analysis, IDH1 expression in tumors could enhance the prognostic accuracy of these factors, including SSIGN outcome algorithm, TNM stage, N stage, Fuhrman grade and tumor sizes. Moreover, two prognostic nomograms models were constructed to predict OS and RFS of ccRCC patients, via integrating IDH1 with significant factors based on the multivariate analysis. Further c-index analysis indicated two prognostic nomograms had better prognostic capability compared with SSIGN prognostic model.

In mammal cells, three types of IDHs were discovered, including IDH1, IDH2, and IDH3. Although these three enzymes show the similar enzymatic reaction, they have different functions in different places. IDH1 performs its enzymatic activity mainly in the cytosol and the peroxisomes [28]. In recent years, mutations in IDH1 gene were reported in various tumors, which confer IDH1 the new enzymatic function of catalyzing α-KG to R-2-hydroxyglutarate (2-HG) [29]. The role of IDH1 gene mutation in esophageal squamous cell carcinoma [30], glioma [31] and acute myeloid leukemia (AML) have been successively reported [32]. The expression level of IDH1-R132H, which is the most common mutation type, correlates with poor outcomes in several cancers, such as gastrointestinal cancer and nonenhancing diffuse glioma [16, 33]. Besides, IDH1 wide-type expression was also explored in tumors. Overexpression of IDH1 was reported in non-small cell lung (NSCL) cancer, both in plasma and tumor tissues [17, 34]. However, our study revealed that low expression of IDH1 was associated with adverse ccRCC patients’ prognosis, which was inconsistent with that in NSCL cancer. Similarly, down-regulation of IDH1 was detected in kidney cancer [35], which means the loss of IDH1 expression might contribute ccRCC genesis.

The mechanism of low IDH1 participates in progression of cancers has not been well elaborated. IDH1 not only plays an important role on the biosynthesis of central metabolites in the tricarboxylic acid (TCA) cycle, but represents the major pathway for cellular NADPH generation in cells, a vital factor that regulates the amount of glutathione (GSH) and thioredoxin in cells [36]. GSH and thioredoxin are the main members of antioxidative systems, which could protect cells from oxidative damages by eliminating the reactive oxygen species (ROS) [37, 38]. Thus, loss the enzymatic function of IDH1 in tumor cells could impair detoxification procedure, which may result in DNA damages and genes mutations [39]. Besides, IDH could also regulate cellular apoptosis, and facilitate the development of a modifier of cancer chemotherapy [40].

Although the clinical significance of IDH1 in ccRCC was revealed, several limitations still exist in our study. Firstly, it is a retrospective cohort in a single center with limited patients, especially for the patients with advanced ccRCC. Therefore, patients from multicentric cohort are necessary to confirm our findings. Secondly, our study was based on the IHC staining and scored by two pathologists, and it would be more persuasive by measuring the mRNA or protein expression level of IDH1. Another problem is that, the time of patients follow up is not long enough to illustrate the clinical significance of IDH1, and longer follow up time is in need. Thus, more researches, especially mechanism studies, are needed to further understand the role of IDH1 in ccRCC progression.

In conclusion, we revealed low expression of IDH1 was significantly associated with poor ccRCC prognosis and could be used as a prognostic parameter to predict ccRCC patients’ outcomes. We also constructed two nomograms for ccRCC patients, which might be adapted into risk scoring systems and guide in clinical decisions for ccRCC patients.