In the present study, we identified the plasma mRNA levels of DDX11, which is involved in cellular growth and division, as an independent prognostic factor for high visceral adiposity even after adjusting for clinicopathological parameters that are significantly associated with adiposity. To the best of our knowledge, this is the first study to investigate the association between the expression of genes potentially involved in ccRCC and adiposity, as well as to use visceral adiposity as a marker to infer the aggressiveness of small ccRCC.
BMI increases the relative risk for RCC [22]. However, the association between BMI and RCC prognosis remains controversial. Prior studies have mainly reported the proportional associations between BMI and RCC prognosis, whereas inverse, flat, or null associations have also been reported [23]. The inconsistencies among the results reported by these studies may be attributed to the use of BMI as a surrogate marker for obesity. Among various types of adipose tissue, VAT is the largest endocrine organ and produces hormones and cytokines that are related to carcinogenesis and tumor progression [15]. Subcutaneous adipose tissue and VAT share scant functional similarities other than their efficiency in energy storage [24]. VAT releases high levels of adipokines that are involved in inflammation and angiogenesis, including interleukin-6, vascular endothelial growth factor, and plasminogen activator inhibitor 1 [24]. In our study, BMI was not significantly correlated with VAT, indicating that the use of BMI would not provide consistent results in assessing the association between obesity and RCC prognosis. Among anthropometric measurements, the VAT content measured via CT has recently been examined for its utility in predicting the risk of cancer.
Five studies have examined the VAT content in patients with localized and/or advanced RCC [25]. Among these, three reported that low VAT contents are associated with poor prognosis in patients with RCC [25], and one study reported no association between VAT contents and overall mortality [26]. Park and colleagues reported that the lowest and the highest vs. the second quartiles of the VAT% are associated with a higher risk of recurrence [23]. Most studies have reported better prognosis in patients with high obesity, especially in those with localized SRMs [11, 23]. Moreover, Parker et al. reported that, in terms of aggressiveness, high BMI is associated with the presentation of a less aggressive form of RCC [9].
Among 28 studies that analyzed the body composition regarding the clinical outcomes of RCC in October 2016, nine studies used fat index, which is the fat area divided by the height of the patients [25]. Since 19 studies used the fat area, we used it as well. However, there could be some bias in using only the fat area, not adjusted to the height of the patients, although our analysis of VAT index showed a non significant association with ISUP grades (P = 0.073).
Although subcutaneous adipose tissue is not associated with perioperative outcomes and survival in RCC, for other cancers, subcutaneous adipose tissue is reportedly associated with cancer-survival outcomes. Takamasa et al. reported that high subcutaneous adipose tissue volume in hepatocellular carcinoma is associated with better survival outcomes when treated with transcatheter intra-arterial therapies [27]. Moreover, leptin and adiponectin, which play a role in cancer biology, are both influenced by VAT and the subcutaneous adipose tissue [28, 29]. Therefore, although subcutaneous adipose tissue is not significantly associated with aggressive RCC, we should not overlook the unidentified importance of the subcutaneous adipose tissue.
DDX11 expression, which is involved in cell-cycle progression, is used to predict tumor aggressiveness in clinically localized T1-stage ccRCC [16, 17]. Additionally, the inhibition of DDX11 expression decreases the proliferation rate of melanoma cells and induces apoptosis [30]. In patients with lung adenocarcinoma, upregulated DDX11 expression is associated with poor prognosis [31].
Consistent with the results of previous studies, our present study showed an inverse relationship between high visceral adiposity and the expression of DDX11 mRNA in the frozen tissues and plasma. Previously, we showed that aggressive ccRCC, such as that associated with synchronous metastasis, recurrence, and/or cancer-specific death, is also associated with the upregulated expression of DDX11 mRNA in both plasma and frozen tissues. Most studies showed that high VAT contents are associated with improved prognosis; thus, we suggest that less aggressive ccRCC is likely associated with high VAT contents. The results obtained in our present study indicated that non-aggressive ccRCC is associated with high VAT contents and low expression of DDX11. Based on these results, conservative therapeutic options, such as ablation and active surveillance, would be prudent strategies for treatment of patients with small ccRCC, a high VAT, and decreased DDX11 expression.
The underlying mechanism that links visceral adiposity to the upregulation of DDX11 expression is unknown. DDX11, a DNA-dependent ATPase and helicase, plays an important role in the cohesion of chromosome arms and centromeres [32]. The depletion of DDX11 results in mitotic failure because the replicated chromosomes fail to segregate after prometaphase [32]. DDX11 expression may be associated with the G1–S phase of the cell-cycle and the pathways involved in DNA replication [32]. Recent studies suggest that adipocyte differentiation, lipogenesis, and lipolysis are strongly modulated by cell-cycle regulators, which control the checkpoints for cell duplication [33]. Our results suggest that DDX11, which is involved in cell-cycle regulation, may be associated with VAT generation. Because the exact pathways connecting cell-cycle regulation and adiposity remain unknown, future studies should elucidate the mechanisms underlying visceral adiposity and DDX11 expression.
Our study was the first to evaluate the association between visceral adiposity and mRNA expression of target genes. Moreover, our results enabled us to easily infer the aggressiveness of ccRCCs using visceral adiposity calculated from preoperative CT without any invasive diagnostic modalities.
Our study has a few limitations. First, the ITH of primary tumors is a considerable problem, even in SRMs [25]. ITH causes sampling bias in conventional needle biopsies. Clinical trials are currently examining the use of circulating tumor DNA in plasma to overcome the limitations imposed by ITH. Second, we could not use visceral adiposity and target-gene expression to predict prognostic indexes, such as cancer-specific or progression-free survival, in patients with ccRCC, owing to the short follow-up period. Third, the study population was relatively small. Future studies should investigate the correlations among visceral adiposity, target-gene expression, and prognosis in large populations of patients with ccRCC.