Comprehensive gene expression analysis for exploring the association between glucose metabolism and differentiation of thyroid cancer

doi:10.21203/rs.2.10560/v1

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Comprehensive gene expression analysis for exploring the association between glucose metabolism and differentiation of thyroid cancer

https://doi.org/10.21203/rs.2.10560/v1

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published 30 Dec, 2019

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Background

The principle of loss of iodine uptake and increased glucose metabolism according to dedifferentiation of thyroid cancer is clinically assessed by imaging. Though these biological properties are widely applied to appropriate iodine therapy, the understanding of the genomic background of this principle is still lacking. We investigated the association between glucose metabolism and differentiation in advanced thyroid cancer as well as papillary thyroid cancer (PTC).

Methods

We used RNA sequencing of PTC obtained from the Cancer Genome Archives and microarray data of poorly-differentiated and anaplastic thyroid cancer (PDTC/ATC). The signatures of GLUT and glycolysis were estimated to assess glucose metabolic profiles. The glucose metabolic profiles were associated with tumor differentiation score (TDS) and BRAFV600E mutation status. In addition, survival analysis of glucose metabolic profiles was performed for predicting recurrence-free survival.

Results

In PTC, the glycolysis signature was positively correlated with TDS, while the GLUT signature was inversely correlated with TDS. These correlations were significantly stronger in the BRAFV600E negative group than the positive group. Meanwhile, both GLUT and glycolysis signatures were negatively correlated with TDS in advanced thyroid cancer. The high glycolysis signature was significantly associated with poor prognosis in PTC in spite of high TDS. The glucose metabolic profiles are intricately associated with tumor differentiation in PTC and PDTC/ATC.

Conclusions

As glycolysis was an independent prognostic marker, we suggest that the glucose metabolism features of thyroid cancer could be another biological progression marker different from differentiation and provide clinical implications for risk stratification.

Cancer Biology

Glucose metabolism

thyroid cancer

tumor differentiation

glycolysis

GLUT

Molecular imaging has been widely used for the biological characterization of thyroid cancer in the clinic. Iodine and glucose metabolism have been respectively identified by radioactive iodine imaging and 2-deoxy-2-[¹⁸F]fluoro-D-glucose (FDG) positron emission tomography (PET), which have played important role in therapeutic plan (1, 2). The fact that thyroid cancers with poor differentiation have lower I-131 avidity and higher F-18 FDG avidity have long been used to presume the aggressiveness of thyroid cancer (3). This ‘flip-flop phenomenon’ was thought to have resulted from the loss of I-131 concentration capacity with increasing demand for glucose during the dedifferentiation of tumor cells (4).

As metabolic features of thyroid cancer could be associated with genomic alteration as well as tumor differentiation, previous studies have revealed the trend of relationship by using imaging studies and pathologic profiles (3, 5, 6). Among the major cancer drivers of differentiated thyroid cancers, B-type Raf kinase (BRAF) mutation exclusively occurred in papillary thyroid cancer (PTC) and PTC-derived anaplastic thyroid cancer (ATC) is associated with low iodine avidity (3). Thyroid cancer with BRAF mutation acquires more aggressive features through BRAF mutation-associated silencing of thyroid-specific genes, differentiation markers of iodine metabolism (6). The dedifferentiation according to BRAF mutation leads to increased glucose consumption of cancer cells (1), which is supported by the finding that PTC with BRAF mutation showed a trend of more FDG avidity (7). In spite of these cross-sectional studies using imaging, there is a lack of comprehensive understanding of the association between tumor glucose metabolism, differentiation and BRAF mutation. Meanwhile, recent comprehensive analyses using next generation sequencing have revealed new integrative molecular subtypes as well as cancer drivers (8). In this regard, the integrative analysis of iodine and glucose metabolism based on the systemic gene expression data is needed for the molecular background of imaging and therapy of thyroid cancer.

The aim of this study is to identify the association between the glucose metabolism profile and the differentiation of thyroid cancer using transcriptomic signatures. As tumor glucose metabolism clinically assessed by FDG PET is associated with the expression of glucose transporters (GLUT) and glycolysis pathways (9-11), gene signatures of GLUT and glycolysis were used for defining glucose metabolic profiles of the tumors. We investigated whether the glucose metabolic profiles were correlated with tumor differentiation and BRAF mutations in advanced thyroid cancer as well as PTC. We also investigated whether these metabolic profiles were associated with clinical outcome, and eventually aimed to redefine the biological progression of thyroid cancer in terms of glucose metabolism as well as differentiation related with iodine uptake.

Subjects and data acquisition

RNA sequencing data of well differentiated papillary thyroid cancers (THCA) were obtained from The Cancer Genome Atlas (TCGA) which was publicly available. The gene expression data of 21,022 genes and clinical information from 505 patients with papillary thyroid cancer were downloaded from the TCGA portal (http://portal.gd.cancer.gov/) using ‘TCGABiolinks’ R/Bioconductor package. Microarray data of poorly differentiated thyroid cancer (PDTC) and ATC were also obtained in NCBI’s Gene Expression Omnibus (GEO) Series accession number GSE76039. Clinical information of PDTC/ATC patients was downloaded from cBioPortal (http://www.cbioportal.org/public-portal).

Glucose metabolic profiles

We normalized mRNA transcripts counts to adjust GC-content effects and between-lane distributional difference. Using normalized gene counts, we calculated the enrichment scores of glucose metabolic signatures for GLUT and glycolysis. Glycolysis signatures were defined by Reactome pathway (12). To estimate the enrichment score of glycolysis, a single sample gene set enrichment analysis (ssGSEA) was performed using the curated gene sets of glycolysis signatures(13). This analysis was performed with GSVA R/Bioconductor package (14). For estimating GLUT score, the sum of log-expression values of GLUT1 and GLUT3 was used as FDG uptake is dependent on these two GLUT subtypes (15). Tumor differentiation score (TDS) were also calculated by expression values of a set of specific genes (8).

Statistical analysis

Student’s t-test was used to analyze whether the signatures of glucose metabolism were significantly different according to the genetic mutation status of BRAFV600E. Pearson’s correlation test was performed to evaluate the associations between TDS and signatures of glucose metabolism. The difference between two correlation coefficients regarding BRAFV600E was calculated by Fisher z-transformation. The effect of the signatures of glucose metabolism on patients’ disease free survival was analyzed using the Cox proportional hazard model. Patients were divided into two groups; lower or higher than the median value of GLUT, and glycolysis unit. Kaplan-Meier survival curves were demonstrated to compare disease free survival between two groups. The statistical significance was evaluated using the Log rank test. The differences between groups were considered statistically significant at p-value < 0.05.

To evaluate the association between tumor differentiation and glucose metabolism in the thyroid cancer, we used two cohorts, papillary thyroid cancer samples of TCGA and PDTC/ATC samples obtained by GEO (GSE76039). The clinical and pathological characteristics of PTC patients and PDTC/ATC patients are summarized in Table 1 and Table 2.

Firstly, GLUT and glycolysis enrichment scores were estimated by gene expression data of the two cohorts and associated with the mutation status, BRAFV600E. The enrichment scores of GLUT and glycolysis were significantly different in PTC according to BRAFV600E mutation status (Figure 1). BRAFV600E positive PTC have higher GLUT signature and lower glycolysis signature (BRAFV600E positive group 20.5±1.1 vs. BRAFV600E negative group 19.1±1.5, t = -12.093, p < 0.0001 for GLUT; BRAFV600E positive group -0.28±0.77 vs. BRAFV600E negative group 0.24±1.11, t = 6.057, p < 0.0001 for glycolysis) than BRAFV600E negative PTC (Figure 1).

To evaluate the tumor differentiation, we employed tumor differentiation score, TDS, calculated by sixteen genes related to thyroid functions. The TDS was compared with glucose metabolic profiles. In PTC group, the TDS was negatively correlated with GLUT signature, but positively correlated with glycolysis signature (r = -0.585, p < 0.0001 for GLUT; Figure 2A, r = 0.334, p < 0.0001 for glycolysis; Figure 2B). We divided PTC into two subgroups according to the BRAFV600E mutation status. PTC with BRAFV600E showed a negative correlation between TDS and GLUT (r = -0.570, p < 0.001), while it showed a positive correlation between TDS and glycolysis (r = 0.352, p < 0.001). PTC without BRAFV600E showed a trend of negative correlation between GLUT and TDS (r = -0.177, p = 0.065) and no significant correlation between glycolysis and TDS. These correlations were significantly stronger in BRAFV600E negative group than positive group (z = 5.22 for GLUT, z = -4.48 for glycolysis, and p < 0.001 for both GLUT and glycolysis; Figure 2C-F). In PDTC/ATC group, the relationship between the TDS and GLUT signature showed a significant negative correlation (r = -0.682, p < 0.0001; Figure 2G). The TDS also showed a significant negative correlation to the glycolysis signature (r = -0.384, p = 0.019; Figure 2H). We also evaluated whether different cell types of PTC were associated with glucose metabolic signatures. Classical cell type PTC have higher GLUT signature and lower glycolysis signature than follicular cell type PTC (Classical cell type 20.1±1.3 vs. Follicular cell type 18.4±1.2, t = 11.547, p < 0.001 for GLUT; Classical cell type -0.13±0.94 vs. Follicular cell type 0.52±1.12, t = -5.653, p < 0.001 for glycolysis; Additional file 1: Figure S1A, B). The negative correlation between TDS and GLUT and the positive correlation between TDS and glycolysis were found in both cell types, classical and follicular types. The strength of their correlations showed no significant difference (Classical cell type: r = -0.467, p < 0.001 for GLUT, r = 0.228, p < 0.001 for glycolysis; Follicular cell type: r = -0.431, p < 0.001 for GLUT, r = 0.338, p = 0.001 for glycolysis; Additional file 1: Figure S1C, D). Individual genes that constitute TDS and glucose metabolic pathway were represented by heatmaps (Figure 3).

We assessed the association between signatures of glucose metabolism and patients’ prognosis. Kaplan-Meier survival curves of both PTC and PDTC/ATC patients with low glycolysis signature showed significantly better survival than the other group (p = 0.045, p = 0.015, respectively; Figure 4A, B). The hazard ratios (H.R.) of the influence of the glycolysis signature on the recurrence of PTC are presented in Table 3. In PTC, the high glycolysis signature alone had a significant influence on the recurrence-free survival (H.R. = 1.497; C.I. = 1.034–2.167; p = 0.033). The adjustment for age and gender maintained its influence on the recurrence-free survival (H.R. = 1.497; C.I. = 1.038–2.160; p = 0.031). Additional adjustment for T-stage and N-stage still demonstrated worse prognosis on PTC patients with high glycolysis (H.R. = 1.915; C.I. = 1.223–2.999; p = 0.005). GLUT score showed no significant correlation with PTC patients’ prognosis (p = 0.85; Figure 4C). On the contrary, we found that PDTC/ATC patients with low GLUT signature have significantly longer disease free survival than the other group (p = 0.0063; Figure 4D).

In this study, we used transcriptome data of thyroid cancers of two cohorts, PTC and PDTC/ATC to evaluate glucose metabolic profiles and tumor differentiation. In PTC, a trend of higher GLUT and lower glycolysis was found in tumors with BRAFV600E mutation and those with relatively poor differentiation. The results of TDS positively correlated with glycolysis and negatively correlated with GLUT were particularly found in PTC without BRAFV600E mutation. Moreover, the high glycolysis enrichment was significantly associated with poor clinical outcome, even it was associated with well differentiation in PTC. However, this paradoxical opposite direction of correlation was not found in PDTC/ATC cohorts, which showed both GLUT and glycolysis were negatively correlated with TDS and associated with poor clinical outcome.

We have found that thyroid cancers with poor differentiation showed higher GLUT expression (Figure 2). Cancer cells demand a higher amount of energy according to the progression, which is associated with enhanced aerobic glycolysis in the advanced cancer (16). The glucose demand of cancers cause overexpression of GLUT1 and/or GLUT3 to increase glucose influx (17). Our results were compatible with the previous studies since poorly differentiated thyroid cancers would need higher glucose uptake through GLUT expression (18). On the other hand, glycolysis signatures of thyroid cancers with poor differentiation were inconsistent between PTC and PDTC/ATC (Figure 2). In PTC, relatively well-differentiated tumors, glycolysis was positively associated with TDS. In PDTC/ATC, a negative correlation was shown between TDS and glycolysis. Considering PTC of TCGA data are relatively well-differentiated tumors compared with PDTC/ATC cohort, the association between the differentiation and glycolysis might have ‘U shape’ pattern; high glycolysis signatures were shown in ATC and some types of well-differentiated PTC. Moreover, increased glycolysis was associated with poor clinical outcome in spite of high TDS. It implies that the differentiation of thyroid cancer may not be the only factor that reflects the biological progression of thyroid cancer. Instead, in addition to differentiation, glucose metabolic profiles represented by glycolysis should be further considered to infer the progression of thyroid cancer, particularly for the specific subtypes of PTC, BRAFV600E negative and/or follicular variants.

Our results demonstrated that the signatures of GLUT and glycolysis can act as prognostic factors in predicting disease free survival of thyroid cancer patients (Figure 4). Notably, these profiles can be noninvasively estimated by FDG PET. GLUT score, calculated by GLUT1 and GLUT3, is the major deterministic factor fort the FDG uptake in various studies (10, 15, 18, 19). Furthermore, glycolysis activity is also associated with FDG uptake in vivo (19, 20). According to the kinetic model of FDG, glycolysis activity is associated with FDG retention, which can be visualized by dual-time FDG PET (21, 22). In general, poorly differentiated thyroid cancers are known to have a worse outcome as compared to well differentiated thyroid cancers (23). However, a subset of well-differentiated carcinoma shows relatively poorly outcome in tumors with increased glycolysis with well-differentiated type. As GLUT and glycolytic activity were differently associated with TDS, noninvasive characterization using FDG PET and radioactive iodine imaging could play a role in risk stratification as well as biological characterization of the tumor. As a future work, more specifically, dual-time FDG PET could be used for estimating glycolysis activity, which might identify a subtype of the tumor with enhanced glycolysis and well-differentiation.

Although, we analyzed glucose profiles of thyroid cancer in the two different cohorts with different differentiation, there are some limitations. Firstly, the PDTC/ATC sample size was small. Though we found the expected role of GLUT and glycolysis on the prognosis of PDTC/ATC patients, further studies with a larger group are needed. Another limitation was that the transcriptome data from two cohorts were not be combined and analyzed since those data were obtained from different resources, RNA sequencing and microarray. Furthermore, noninvasive imaging biomarkers using iodine scan and FDG PET integrated with transcriptomic data could clarify our results of the association of differentiation and glucose metabolic profiles.

According to the integrative analysis of iodine and glucose metabolism based on the systemic gene expression data, metabolic profiles were not simply associated with tumor differentiation. Cancer cellular GLUT expression was negatively associated with tumor differentiation in both PTC and PDTC/ATC. The enrichment of glycolysis was positively associated with the differentiation in well-differentiated PTC, while it was negatively associated with the PDTC/ATC. Overall, there might be ‘U-shape’ pattern for the association of the differentiation and glycolysis. Furthermore, increased glycolysis was poor prognosis in spite of the well-differentiated tumor. We anticipate that the biological and prognostic characteristics of glucose metabolic profiles could provide insight for biomarker using FDG PET and appropriate therapeutic plan.

FDG: 2-deoxy-2-[18F]fluoro-D-glucose

PET: positron emission tomography

BRAF: B-type Raf kinase

PTC: papillary thyroid cancer

ATC: anaplastic thyroid cancer

GLUT: glucose transporter

THCA: well differentiated papillary thyroid cancer

TCGA: The Cancer Genome Atlas

PDTC: poorly differentiated thyroid cancer

GEO: Gene Expression Omnibus

ssGSEA: single sample gene set enrichment analysis

TSD: tumor differentiation score

H.R.: hazard ratio

HK: hexokinase

C.I. = Confidence Interval

Ethics approval and consent to participate

Patient data we used were acquired by a publicly available dataset that removed patient identifiers. The publicly available data were collected with patients’ informed consent approved by the institutional review boards of all participating institutions following 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available in the TCGA Research Networks: http://cancergenome.nih.gov/ and GEO: http://www.ncbi.nlm.nih.gov/geo.

Competing interests

The authors declare that they have no competing interests.

Funding

Funding was provided by Seoul National University Hospital Research Fund (grant no. 2620180060).

Authors’ contributions

HC designed the study. HYS and HC acquired and analyzed data, and drafted the manuscript. JCP, GJC, JC, and KWK participated in discussion and provided critical revision. All authors read and confirmed the manuscript.

Acknowledgements

The results here are in based upon data generated by the TCGA Research Network: “http://cancergenome.nih.gov/”.

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Table 1. Clinicopathological characteristics of the 505 PTC included in the study

Variables	PTC	No. of available data
Gender (M:F)	136 : 369	505
Age (years)	46.89±15.84 (15.38–89.54)	505
Race
White / Asian / Black / Etc.	334 / 51 / 27 / 1	413
Histology
Classical / Follicular / Tall cell / Other	323 / 99 / 34 / 9	465
BRAFV600E (Positive:Negative)	235 : 270	505
Stage
1 / 2 / 3 / 4	284 / 52 / 112 / 55	503
Recurrence-free survival time (months)	14.26 (0–158.71)	344

PTC = Papillary Thyroid Cancer

Variables	PDTC/ATC	No. of available data
Gender (M:F)	10 : 27	37
Age (years)	69±13.74 (27–87)	37
Race
White / Asian / Black / Etc.	NA
Histology
Papillary / Follicular / Tall cell / Other	14 / 5 / 5 / 5	29
BRAFV600E (Positive:Negative)	NA
Stage
1 / 2 or 3 / 4	1 / 5 / 24	30
Recurrence-free survival time (months)	10.3 (0.23–223.49)	35

Table 2. Clinicopathological characteristics of the 10 PDTC and 27 ATC included in the study

PDTC/ATC = Poorly-Differentiated Thyroid Cancer/Anaplastic Thyroid Cancer

Table 3. Hazard ratio of glycolysis signature for the recurrence of PTC

	Hazard Ratio of high glycolysis signature group (95% C.I.)	p-value
Unadjusted	1.497 (1.034–2.167)	0.033
Adjusted for age and gender	1.497 (1.038–2.160)	0.031
Adjusted for age, gender, T-stage, and N-stage	1.915 (1.223–2.999)	0.005

PTC = Papillary Thyroid Cancer; C.I. = Confidence Interval

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Editorial decision: Major revision
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Reviewer #2 agreed at journal
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Reviewer #1 agreed at journal
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Comprehensive gene expression analysis for exploring the association between glucose metabolism and differentiation of thyroid cancer

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