High levels of total cholesterol in the serum as a predictor of poor survival in patients with glioma

doi:10.21203/rs.3.rs-3872970/v1

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High levels of total cholesterol in the serum as a predictor of poor survival in patients with glioma

https://doi.org/10.21203/rs.3.rs-3872970/v1

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Introduction

The alteration of lipid profiles has been documented to be associated with the incidence of various cancers. However, the prognostic value of pre-operative serum total cholesterol (TC) in glioma patients has not been reported.

Material and methods

Pre-operative serum lipid and lipoprotein concentrations, including TC, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and ApoA-I, were retrospectively analyzed in 221 patients with glioma and compared with 218 healthy controls. The Cox proportional hazards model and log-rank test were performed to analyse the prognostic value of serum lipid levels in patients with glioma.

Results

Compared with healthy control patients, the levels of TC and LDL-C were statistically significantly lower in patients with glioma. Serum TC concentrations were significantly higher in patients with glioma recurrence than in patients whose disease did not recur. Univariate and multivariate analyses indicated TC level, WHO grade, post-operative chemoradiotherapy and age to be independent prognostic factors that were correlated with shorter overall survival. In addition, TC level, WHO grade and age were identified as prognostic factors associated with recurrence-free survival in the multivariate analysis.

Conclusions

Increased pre-operative TC concentrations were found to be associated with poorer long-term survival in patients with glioma. Ultimately, our findings indicate that, in glioma patients, the evaluation and control of serum lipids may provide prognostic and therapeutic value respectively.

total cholesterol

glioma

lipids

overall survival

recurrence-free survival

Glioma is the most common malignant primary tumor in the central nervous system, presenting a serious health burden both in terms of mortality and morbidity. Based on the clinical and histopathological criteria established by the World Health Organization (WHO), glioma is classified from grade Ⅰ to grade Ⅳ [1]. Despite multiple therapeutic strategies, high-grade glioma (WHO grade ⅠⅠⅠ and grade Ⅳ) patients still tend to have a very poor prognosis. The median survival time for grade Ⅳ glioma is just 16 months and 5-year overall survival is less than 10% [2, 3]. With developments in molecular pathology, several biomarkers – such as epidermal growth factor receptor (EGFR), 1p19q co-deletion, and isocitrate dehydrogenase 1 – can routinely be applied. This empowers physicians to provide a more individualized therapeutic strategy and accurate prognostic assessment for each patient [4]. However, the variety of biomarkers for glioma is relatively limited. Thus, identifying more specific and sensitive biomarkers is of vital importance.

A series of epidemiological studies have demonstrated that abnormal levels of lipids are closely correlated with the risk of colon, prostate and nasopharyngeal carcinoma. Furthermore, cholesterol synthesis is associated with cancer development and metastasis. Indeed, accumulating evidence has suggested dysregulated lipid metabolism to be a hallmark of cancer [5, 6]. Total cholesterol (TC) is localized in lipid rafts-membrane micro-domains. Its function is to assemble the signal transduction machinery. Cell biological studies support a critical involvement of cholesterol in the modulation of proteins implicated in key cellular signaling pathways. This pathway organization can lead to malignant transformation, including colon, breast and nasopharyngeal cancers, due to cell polarity, altered cytoskeleton and angiogenesis [7]. Glioma tumor tissues contain higher levels of unsaturated fatty acids compared with the normal brain. However, the prognostic role of TC in patients with glioma remains unclear. This study was designed to elucidate any possible correlations between in vivo lipid metabolism and the occurrence of glioma. This was done by comparing the serum lipid concentrations found in glioma patients prior to surgery with healthy participants.

2.1 Patients

Between January 2008 to December 2013, 221 patients with glioma were recruited prior to undergoing glioma removal surgery at the first affiliated hospital of JiNan University, located in Southern China. Inclusion criteria included: (1) patient age ≥ 18 years; (2) a pathological, confirmed diagnosis of glioma with no previous or coexisting cancer. Patients taking hormone replacement therapy or any drugs known to affect lipid metabolism were excluded from this study. We retrospectively recorded and reviewed patients’ age, gender, pathological information, WHO grade, smoking and alcohol status, overall survival and recurrence-free survival data.

2.2 Laboratory measurements

Peripheral blood was collected from the patients between 7 and 8 a.m, before any therapy, and centrifuged at 3500 r/min for 8 min. The serum concentrations of TC, triglycerides (TG), ApoA-I, HDL-C and LDL-C were measured using a Hitachi 7600 automatic biochemical analyzer. Serum TC was measured by the CHOD-PAP method and Serum TG was measured by the GPO-PAP method. ApoA-I was measured by immunoturbidimetry; HDL-C and LDL-C were detected using the selective elimination method (direct method) and selective protection method, respectively. All reagents used in this study were provided by Wako Pure Chemical Industries, Japan.

2.3 Statistical analysis

Statistical analysis was conducted to identify any factors that may be associated with poor survival of patients with glioma. Data were presented as the mean and standard deviation (mean ± SD). The correlation between TC and clinical characteristics was quantified by Mann–Whitney U test and X² test. Overall survival (OS) was calculated based on the number of individuals surviving between the first diagnosis of glioma and the last date of follow-up. The event for recurrence-free survival (RFS) was the duration between the date of being diagnosed and the date of having events of loco-regional recurrence or the last date of follow-up. Continuous variables were categorized using median values. The differences between glioma patients and healthy donors were compared using unpaired Student’s t-tests. Univariate and multivariate analyses of clinical variables were performed using Cox proportional hazards regression models. Survival analysis was performed using the Kaplan–Meier method and comparisons were calculated using the log-rank test. P values < 0.05 were considered to indicate statistically significant differences. All reported P values are two-sided.

At the last follow-up, 102 (46.1%) of the 221 patients had died and 110 (49.8%) had events of loco-regional recurrence. For both glioma patients and healthy control patients, the associations between median serum TC levels and clinical variables are shown in Table 1. In the entire cohort, age, gender, WHO grade and tobacco and alcohol status had no influence on baseline TC level. However, for tumor recurrence patients (5.71 ± 1.36 mmol/L), the serum TC levels were lower than that in recurrence-free patients (4.93 ± 0.98 mmol/L, P < 0.05).

Table 1

the levels of TC between the glioma patients and healthy controls
characteristics	glioma		P value	controls		P value
	numbers	Median(rang)		numbers	Median(rang)
Age, years			0.213			0.773
< 60	190	5.11(5.59–9.81)		192	5.53(3.27–8.92)
≥ 60	31	5.21(3.22–8.30)		26	5.44(3.78–8.72)
Gender			0.414			0.089
male	134	5.29(2.59–9.33)		109	5.75(3.27–8.72)
female	87	5.01(3.22–9.81)		109	5.40(3.73–8.92)
Who grade			0.089
Ⅰ-Ⅱ	83	4.79(3.10–7.93)
Ⅲ-Ⅳ	138	5.32(2.59–9.81)
tobacco			0.096
yes	64	5.10(3.22–7.99)
no	157	5.21(2.59–9.81)
alcohol			0.806
yes	39	4.88(3.32–8.84)
no	182	5.21(2.59–9.81)
recurrence			0.005
yes	110	5.58(3.10–9.81)
no	111	4.84(2.59–7.99)

To investigate whether lipid abnormalities occur in glioma patients, the levels of lipids were compared between the glioma (n = 218) and healthy control (n = 221) patients (Table 2). The mean concentration of TC in glioma patients was 5.32 ± 1.25 mmol/L, significantly lower than that of the healthy control group (5.58 ± 1.01 mmol/L, P = 0.007). Furthermore, the level of LDL-C (3.36 ± 1.23 mmol/L) in glioma patients was also significantly lower than that in healthy control patients (3.53 ± 0.93 mmol/L, P = 0.023) (Fig. 1).

Table 2

the levels of lipids between the glioma patients and healthy controls
	glioma		normal		P value
	Median	(rang)	Median	(rang)
TC (mmol/L)	5.11	2.59–9.81	5.52	3.27–8.92	0.006
TG (mmol/L)	1.09	0.27–8.82	1.15	0.4-12.91	0.158
HDL-C(mmol/L)	1.26	0.65–2.59	1.29	0.7–2.48	0.281
LDL-C(mmol/L)	3.19	1.22–8.89	3.47	1.42–6.55	0.047
ApoA-l(g/L)	1.21	0.67-2.00	1.51	0.98–2.25	0.305

A univariate and multivariate Cox regression model was used to evaluate the prognostic value of the lipids in glioma patients (Table 3). Input variables included patients’ age, gender, smoking and alcohol status, WHO grade, post-operative chemoradiotherapy and pre-operative serum lipid and lipoprotein concentrations (including TC, TG, HDL-C, LDL-C, ApoA-I) The univariate analysis revealed patients’ age, WHO grade, postoperative chemoradiotherapy and pre-therapy serum levels of TC to be significantly association with patients’ OS. Multivariate analysis found each of these prognostic indicators to be independent of one another.

Table 3

Univariate and multivariate cox analysis for overall survival in patients with glioma
Variables	Univariate analysis			Multivariate analysis
	HR	95%CI	P Value	HR	95%CI	P Value
gender
Male vs female	1.156	0.724–1.845	0.545
age
< 60 vs ≥ 60	2.102	1.287–3.433	0.003	2.119	1.326–3.387	0.002
WHO
Ⅰ-Ⅱ vs Ⅲ-Ⅳ	4.211	2.470–7.179	< 0.05	4.229	2.518–7.101	< 0.05
tobacco
Yes vs no	0.991	0.594–1.653	0.972
alcohol
Yes vs no	0.681	0.382–1.217	0.195
Postoperative chemoradiotherapy
Yes vs no	0.417	0.273–0.637	< 0.05	0.439	0.290–0.664	< 0.05
TC
< 5.11 vs ≥ 5.11	1.754	1.030–2.989	0.039	2.186	1.427–3.350	< 0.05
TG
< 1.09 vs ≥ 1.09	1.210	0.755–1.941	0.428
HDL
< 1.26 vs ≥ 1.26	1.383	0.831–2.302	0.213
LDL
< 3.19 vs ≥ 3.19	1.419	0.825–2.441	1.419
APO
< 1.21 vs ≥ 1.21	1.109	0.714–1.725	0.645

The Kaplan–Meier method was utilized to further explore the prognostic significance of TC level in glioma patients and survival curves plotted. In the glioma patient cohort, patients with TC < 5.11 mmol showed a significantly better 5-year OS than the patients with TC ≥ 5.11 mmol/L. The cumulative 5-year survival rate in the TC < 5.11 mmol patients was 64.0%, whereas it was only 29.3% in the TC ≥ 5.11 mmol/L patients (P < 0.05, Fig. 2).

In addition, the univariate analysis showed younger age, lower WHO grade and lower TC level to be significant, independent predictors for more favorable prognosis for recurrence-free survival (Table 4). Multivariate analysis showed that patients with TC < 5.11mmol showed a significantly better RFS than the patients with TC ≥ 5.11 mmol/L (HR = 2.270, 95% CI = 1.528–3.372; P < 0.05) (Fig. 3).

Table 4

Univariate and multivariate cox analysis for recurrence-free survival in patients
Variables	Univariate analysis			Multivariate analysis
	HR	95%CI	P Value	HR	95%CI	P Value
gender
Male vs female	0.958	0.607–1.514	0.855
age
< 60 vs ≥ 60	1.836	1.117–3.017	0.017	1.901	1.189–3.038	0.007
WHO
Ⅰ-Ⅱ vs Ⅲ-Ⅳ	3.988	2.413–6.591	< 0.05	3.630	2.260–5.831	< 0.05
tobacco
Yes vs no	1.102	0.682–1.783	0.692
alcohol
Yes vs no	0.788	0.465–1.334	0.375
Postoperative chemoradiotherapy
Yes vs no	0.685	0.455–1.033	0.071
TC
< 5.11 vs ≥ 5.11	1.680	1.032–2.736	0.037	2.270	1.528–3.372	< 0.05
TG
< 1.09 vs ≥ 1.09	1.280	0.808–2.029	0.293
HDL
< 1.26 vs ≥ 1.26	1.317	0.794–2.185	0.286
LDL
< 3.19 vs ≥ 3.19	1.531	0.926–2.530	0.097
APO
< 1.21 vs ≥ 1.21	0.968	0.625–1.501	0.885

Glioma is a common primary tumors of the central nervous system[8]. Due to its invasive nature, surgery is seldom capable of removing all tumor cells. This means that glioma tends to re-occur postoperatively [9]. Whilst age, mental status, tumor grade and histology, the extent of surgical resection and radiotherapy regime allow physicians to predict disease course with some accuracy [10–12], few prognostic biomarkers exist in comparison to other cancers.

Hyperlipidemia is a negative prognostic factor for patients with prostate cancer and gastric cancer [13, 14]. Little is known, however, as to the prognosis values of the lipid profiling in glioma patients. Hence, our study retrospectively compared the lipid profiles of glioma patients with those of healthy controls. This revealed TC (5.32 ± 1.25 mmol/L) and LDL-C (3.36 ± 1.23 mmol/L) concentration to be significantly lower in patients with glioma than that in healthy controls. Furthermore, we assessed the association between serum lipid (TC, TG, HDL-C, LDL-C and ApoA-I) concentrations prior to glioma surgical intervention and disease survival. This revealed survival rates to be significantly negatively associated with serum TC concentrations (HR = 2.186, 95% CI = 1.427–3.350; P < 0.05). This correlation was found to be independent of other variables predicting prognosis, suggesting TC to potentially play a causal role in worsened disease prognosis. Consistent with previous works, lower age and WHO grade and the initiation of post-operative chemoradiotherapy were also significant independent predictors of favorable OS [15–17]. In addition, our study showed RFS rates to also be higher in patients with decreased TC levels than in patients with higher TC levels (HR = 2.270, 95% CI = 1.528–3.372; P < 0.05). Thus, our findings indicated that the pre-therapy serum TC level may serve as a novel, independent prognostic factor for glioma patients.

Cholesterol is localized in lipid rafts-membrane micro-domains, which mainly function to assemble the signal transduction machinery. Studies support a critical involvement of cholesterol in the modulation of proteins implicated in key cellular signaling pathways. Furthermore, due to altered cytoskeleton, cell polarity and angiogenesis, these pathways’ organization can lead to malignant transformation, including colon, breast and nasopharyngeal cancer[18–21]. Some studies have indicated a positive association between high levels of total cholesterol (TC) and overall mortality in cancer patients [22]. For example, Zhou et al., [7] found, by pooling patient-level data from > 24,655 individuals, that TC is a negative prognostic factor for OS and disease-free survival (DFS) in patients with cancers. Similarly, the present study also showed a high TC level to be strongly correlated with poor OS (HR = 2.186, 95% CI = 1.427–3.350; P < 0.05) and RFS rates (HR = 2.270, 95% CI = 1.528–3.372; P < 0.05). TC is an independent prognostic factor for both OS and DFS survival of glioma patients.

The role of TC in glioma is not well understood. Cholesterol is a critical component of cell membranes [23]. Furthermore, it acts as a signaling molecule and energy resource, enhancing cell growth [24]. Glioma tumor tissues contain higher levels of unsaturated fatty acids compared with the normal brain. Svenja et [25] found that extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration. NMR provides specific information on the neurochemistry of human tissues. Therefore, NMR has been used to characterize the total lipid fraction of neoplastic and healthy human brain tissue. By utilizing 1H- and 13C-NMR, cholesterol esters, formed by the esterification of cholesterol with long-chain fatty acids, have been shown to only be present in high-grade gliomas [26]. Since levels of free cholesterol are strictly regulated by negative feedback mechanisms, targeting the formation of cholesterol esters could be the potential therapeutic strategy in glioma patients. When cells need cholesterol, cholesterol esters could quickly release cholesterol for cell growth or survival. Since cholesterol esters are absent in healthy brain tissues, preventing cholesterol ester utilization may be a possible therapeutic strategy to inhibit malignant glioma growth [27, 28]. Our study indicated patients with high serum TC concentrations to have a significantly poorer 5-year OS. We additionally found that recurrence was associated with higher serum TC levels (5.71 ± 1.36 mmol/L, P < 0.05). Further research is, however, needed to clarify the underlying causal mechanisms here.

In this study, we found serum TC, a simple and routinely tested blood biomarker, to potentially be a good candidate for the prediction of prognosis in glioma patients. Patients with a higher level of TC had much poorer OS and RFS. However, the mechanism mediating this association need to be further investigated. Nonetheless, our findings may indicate the proper control of serum lipid to be a valuable therapeutic strategy in glioma patients.

Ethics approval and consent to participate

Written informed consent for publication was obtained from all participants. This study was performed according to the Helsinki Declaration and was approved by the Ethics Committee of The First Affiliated Hospital of Jinan Unversity.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author Contribution

Conception and design: Wei-Long Ding.Acquisition of data: Jing Wang. Analysis and interpretation of data: Jun-Bao Yang. Drafting the article: Wei-Long Ding.Reviewed submitted version of manuscript: Jun-Bao Yang. Statistical analysis: Jing Wang. Study supervision: Xiang-Yu Wang.

Data availability

All available data is already presented in the manuscript.

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High levels of total cholesterol in the serum as a predictor of poor survival in patients with glioma

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Abstract

Introduction

Material and methods

Results

Conclusions

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1. Introduction

2. Material and methods

2.1 Patients

2.2 Laboratory measurements

2.3 Statistical analysis

3. Results

4. Discussion

5. Conclusion

Declarations

Funding

Author Contribution

Data availability

References

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