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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 3  |  Page : 644-651

BCL6B hypermethylation predicts metastasis and poor prognosis in early-stage hepatocellular carcinoma after thermal ablation


1 Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
2 Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
3 Department of Interventional Radiology, Affiliated Hospital of Qingdao University, Qingdao, China
4 aDepartment of Ultrasound, Yantai Qishan Hospital, Yantai, China
5 Department of Ultrasound, The First Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China

Date of Submission12-Oct-2020
Date of Decision06-Dec-2020
Date of Acceptance10-Feb-2021
Date of Web Publication9-Jul-2021

Correspondence Address:
Jie Yu
Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing
China
Ping Liang
Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1504_20

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 > Abstract 


Aims: The aim of this study was to evaluate the role of BCL6B methylation in the progression of early-stage hepatocellular carcinoma (HCC) after thermal ablation.
Settings and Design: This is a retrospective study and written informed consent was obtained from all patients or their legal guardians.
Subjects and Methods: Between October 2008 and December 2013, 73 patients with early-stage HCC within the Milan criteria, who received thermal ablation, were recruited.
Statistical Analysis Used: Based on methylation-specific polymerase chain reaction, the relationship between BCL6B methylation and patient characteristics and prognosis was analyzed using univariate, multivariate, and Kaplan–Meier analysis.
Results: The median follow-up period was 56 (8–110) months. For the BCL6B unmethylated group, the 1-, 3- and 5-year metastasis and overall survival (OS) rates after thermal ablation were 10.0%, 10.0%, and 40.0% and 100%, 100% and 90.0%, respectively. The 1-, 3-, and 5-year metastasis and OS rates of the methylated group were 23.8%, 66.7% and 88.9% and 66.2%, 71.4% and 41.3%, respectively. Levels of absolute count lymphocyte, serum cholinesterase and albumin in the BCL6B unmethylated group were higher than those in the methylated group (P = 0.020, 0.000, and 0.009, respectively). Kaplan–Meier analysis revealed that BCL6B methylation was related to metastasis and poor prognosis (P = 0.001 and 0.018, respectively). Univariate analysis revealed that BCL6B methylation was a risk factor for metastasis and poor prognosis (odds ratio [OR]: 5.663; 95% confidence interval [CI], 1.745–18.375, P = 0.004 and OR: 3.734; 95% CI, 1.151–12.110, P = 0.028, respectively). Multivariate analysis revealed that BCL6B methylation was an independent risk factor for metastasis (OR: 3.736; 95% CI, 1.000–13.963,P = 0.05) and not for prognosis (OR: 2.780; 95% CI, 0.835–9.250,P = 0.096).
Conclusions: BCL6B methylation could be a valuable prognostic factor for metastasis and poor prognosis in early-stage HCC after thermal ablation, which is an independent risk factor for metastasis. Our findings provide insights for combining ablation and epigenetic therapy for patients with HCC.

Keywords: BCL6B, hepatocellular carcinoma, hypermethylation, metastasis, prognosis, thermal ablation


How to cite this article:
Li X, Guo M, Yang L, Cheng Z, Yu X, Han Z, Liu F, Sun Q, Han X, Yu J, Liang P. BCL6B hypermethylation predicts metastasis and poor prognosis in early-stage hepatocellular carcinoma after thermal ablation. J Can Res Ther 2021;17:644-51

How to cite this URL:
Li X, Guo M, Yang L, Cheng Z, Yu X, Han Z, Liu F, Sun Q, Han X, Yu J, Liang P. BCL6B hypermethylation predicts metastasis and poor prognosis in early-stage hepatocellular carcinoma after thermal ablation. J Can Res Ther [serial online] 2021 [cited 2021 Jul 29];17:644-51. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/644/321011




 > Introduction Top


Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, has the third highest mortality rate with a 5-year survival rate <12%, and an increasing rate of incidence and mortality.[1],[2] Although HCC surveillance for high-risk populations may contribute to early tumor detection and treatments, including surgical, local thermal ablation, transcatheter arterial chemoembolization and stereotactic body radiation therapy, to reduce mortality rates, clinical outcomes remain unsatisfactory.[3],[4] Most patients with HCC are not surgical candidates and are managed with nonsurgical locoregional interventions, mainly thermal ablation, which is the first-line treatment option for early-stage HCC.[5] However, high recurrence and metastasis rates after treatment are major challenges and lead to dismal prognosis.[6] Predicting the prognosis after ablation and solving the problem are urgently concerns. Prognosis prediction could provide more optimized treatment strategies, and biomarkers could be potential targets for therapeutic intervention, thereby improving prognosis. At present, α-fetoprotein (AFP) is the only commonly used biomarker with limited clinical utility and relatively low sensitivity and specificity.[7] Therefore, other valuable biomarkers must be investigated.

Cancer is driven by genetic abnormalities. However, epigenetic deregulation may play an equally important role.[8] The development of HCC follows a multistep process that often originates from chronic hepatitis, developing to liver cirrhosis and eventually HCC. The multistep process involves a gradual accumulation of genetic and epigenetic alternations leading to the hyperactivation of proto-oncogenes and inactivation of tumor-suppressor genes (TSGs).[9] DNA methylation is a major epigenetic event that occurs in eukaryotic DNA at CpG sites and has been shown to be a common event in HCC due to the functional loss of TSGs.[10],[11] Unlike genetic alterations, epigenetic changes are often reversible, which makes epigenetic therapy an attractive candidate for anti-cancer drug development.[12]

BCL6B, a homologue of B cell CLL/lymphoma 6 (BCL6), is located on chromosome 17p13.1. BCL6B is considered a TSG and methylation of BCL6B may serve as a predictive biomarker in gastric and colorectal cancer.[13],[14],[15],[16] Although the mechanism of BCL6B methylation in liver damage and fibrogenesis, carcinogenesis, migration and metastasis is established, the clinical implications of BCL6B methylation in HCC prognosis has been scarcely analyzed.[16],[17],[18] Although thermal ablation is an effective treatment for HCC and may change the immune and epigenetic microenvironment of patients with HCC,[19],[20] little is known about the association of BCL6B methylation with the clinical prognosis of HCC after thermal ablation. ZNF545 was reported as a TSG in HCC and its methylation may be a valuable new prognostic factor for early-stage HCC after thermal ablation.[21] Given that BCL6B is frequently methylated in human HCC and its expression is regulated by promoter region hypermethylation, we hypothesized that BCL6B methylation contributes to metastasis and poor prognosis in HCC following thermal ablation. Therefore, a comprehensive investigation into the potential prognostic value of BCL6B methylation is warranted.


 > Subjects and Methods Top


Ethics statement

This retrospective study was performed in compliance with relevant laws and institutional guidelines and was approved by the Institutional Review Board of the Chinese PLA General Hospital. Written informed consent was obtained from all patients or their legal guardians.

Clinical specimens

From October 2008 to December 2013, 73 treatment-naive patients with early-stage HCC within the Milan criteria, who received curative thermal ablation (38 radiofrequency and 45 microwave ablation) were recruited in this single-center study and reviewed. A total of 16 women and 57 men with a mean age of 58.8 ± 10.3 years (range, 41–82 years) participated in the study. Patients were identified prospectively and consecutively. HCC tissues were obtained by ultrasound-guided core needle (18-gauge, BARD, USA) biopsy before ablation and pathological diagnosis was verified.

Inclusion criteria were as follows: (1) Eastern Cooperative Oncology Group performance scores ≤2; (2) Child–Pugh grade A or B; (3) single tumor maximum size <5 cm and tumor number <3; (4) absence of vascular invasion or extrahepatic metastasis; (5) ablation technically successful after initial treatment; and (6) no history of other malignancies. The exclusion criteria were as follows: (1) patients who underwent combined with other treatments (surgical, transcatheter arterial chemoembolization, et al.); (2) patients with severe coagulation disorders, with prothrombin time (PT) >25 s, prothrombin activity <40% and platelet count <40 × 109 cells/L); (3) cause of death was not HCC progression; (4) lost during the follow-up. As evaluated by the flow chat in [Figure 1], 28 patients were excluded because they could not meet the inclusion criteria.
Figure 1: The flow chart of patients with early stage hepatocellular carcinoma enrolled in this study

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The clinicopathologic parameters were examined: (1) patient features (sex, age, etiology, differential degree and Child–Pugh grade, (2) tumor size and number and (3) laboratory parameters, including virus load, hemoglobin (HG), absolute count lymphocyte (ACL), glutamic-pyruvic transaminase (Aspartate aminotransferase [AST]), glutamic-oxaloacetic transaminase (Alanine aminotransferase [ALT]), white blood cell (WBC), blood PLA, serum cholinesterase (CHE), albumin (ALB), PT, glutamyltransferase (GGT)), total bilirubin, direct bilirubin, serum Cer, alkaline phosphatase (ALP) and AFP level.

DNA extraction, bisulfite modification, and methylation-specific polymerase chain reaction

The tissues were snap-frozen in liquid nitrogen and stored at −70°C until DNA extraction. Methylation-specific polymerase chain reaction (MSP) were performed as described.[22],[23] MSP primers were designed around the transcriptional start site in the promoter region of BCL6B (NM_181844.3). Primer sequences and results were reported in our previous study.[16]

Ultrasound-guided percutaneous thermal ablation

A cooled-shaft microwave system (KY-2000, Kangyou Medical, Nanjing, China) and a 470-kHz ± 10 multipolar cooled-shaft radiofrequency generator (Celon Lab Power, Celon, Berlin, Germany) were used at our institution. The microwave generator can produce 100 W of power at 2450 or 915 MHz. The needle antenna has a diameter of 1.9 mm, one 18 cm shaft and 5–22 mm exposure tip. The radiofrequency generator can produce 250 W of power output. The electrode shaft diameter is 1.8 mm with a 20 cm length and 2–4 cm exposure tip. Ablation was performed as described.[24] All ablations were performed percutaneously by interventional radiologists (P. L. and X. L. Y., with 25 years of experience).

Follow-up

All patients were followed up after ablation using contrast-enhanced ultrasonography (US), computed tomography, or magnetic resonance imaging at 1 and 3 months after treatment and then at 6-month intervals.[24] In this study, metastasis and death were defined as end points. Metastasis was defined as new intrahepatic and extrahepatic lesions on images. The days between the first session of thermal ablation and death or end of follow-up were used to calculate overall survival (OS). Follow-up was closed at the time of death or the last visit of the patient in September 2019.

Statistical analysis

We compared baseline clinicopathological characteristics between the BCL6B methylated and unmethylated groups in patients with HCC using the t-test or Chi-square test. Relationships between BCL6B methylation and clinicopathological characteristics were compared using correlation analysis. Univariate and multivariate Cox regression analysis were performed to assess the prognostic value of BCL6B methylation. We calculated odds ratios (ORs) for risk of metastasis and OS in HCC following thermal ablation using unconditional logistic regression, progressively adjusted for age, sex, differential, size, number, hepatitis, virus load, HG, ACL, AST, ALT, WBC, PLA, CHE, ALB, PT, GGT, AFP, and Child–Pugh stratification. The association of BCL6B methylation with metastasis and OS was studied using the Kaplan–Meier method with the log-rank test. All statistical analyses were performed using the SPSS 22.0 statistical package for Windows (SPSS, Chicago, IL, USA) by doctors X. L. C. A. and J. Y. P < 0.05 was considered statistically significant.


 > Results Top


Comparison of clinicopathological characteristics between BCL6B methylated and unmethylated groups in patients with hepatocellular carcinoma

Of the 73 patients with HCC, BCL6B methylation was detected in 63 (86.3%), whereas no methylation was detected in 10 (13.7%) cases. Clinicopathological characteristics and BCL6B methylation status were compared between the two groups. Among the 23 indexes, the level of ALB, CHE and ACL in the BCL6B unmethylated group were higher than those in the BCL6B methylated group, with a significant difference (P = 0.020, 0.000 and 0.009, respectively) [Table 1], and the results was verified by correlation analysis.
Table 1: Characteristics of early-stage hepatocellular carcinoma patients in BCL6B unmethylation and methylation groups

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Comparison of metastasis and overall survival rates between the BCL6B methylated and unmethylated groups in patients with hepatocellular carcinoma after thermal ablation

The follow-up period ranged from 8 to 110 months (median 56 months). In the BCL6B unmethylated group, the 1-, 3-and 5-year metastasis and OS rates were 10.0%, 10.0% and 40.0% and 100%, 100% and 90.0%, respectively. By contrast, the 1-, 3-, and 5-year metastasis and OS rates in the BCL6B methylated group were 23.8%, 66.7, and 88.9% and 66.2%, 71.4% and 41.3%, respectively. All results showed higher metastasis and lower OS rates in the BCL6B methylated group. Thus, BCL6B methylation might be an important predictor for metastasis and OS following thermal ablation. Kaplan–Meier analysis revealed that BCL6B methylation in HCC correlated with higher metastasis and low survival rates (P = 0.001 and 0.018, respectively) [Figure 2]a and [Figure 2]b, which further verified the importance of BCL6B methylation in HCC after thermal ablation.
Figure 2: Kaplan–Meier curves of metastasis free survival (a) and overall survival (b) in methylation and unmethylation patients with early stage hepatocellular carcinoma after thermal ablation

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BCL6B methylation is an independent risk factor for metastasis in hepatocellular carcinoma after thermal ablation

Metastasis is a critical factor in poor prognosis after treatment in HCC. Verifying whether BCL6B methylation is an independent factor for metastasis using univariate analysis revealed that BCL6B methylation, age, virus load, AST, and CHE were predictive factors for metastasis (P = 0.018, 0.032, 0.026, 0.007, and 0.026, respectively) [Table 2]. Multivariate analysis revealed that BCL6B methylation and AST were predictive factors (P = 0.050 and 0.017, respectively) [Table 2]. Furthermore, unconditional logistic regression was performed by progressively adjusting for age, sex, differential, size, number, hepatitis, virus load, HG, ACL, AST, ALT, WBC, PLA, CHE, ALB, PT, GGT, AFP, and Child–Pugh stratification and no significant difference was detected between ORs for BCL6B methylation predicating metastasis (P < 0.05) [Table 3]. The results indicated that BCL6B methylation was an independent risk factor for metastasis in HCC after thermal ablation.
Table 2: Univariate and multivariate analysis of variables for metastasis in early-stage hepatocellular carcinoma patients after thermal ablation

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Table 3: Association of bcl6b methylation with metastasis in early-stage hepatocellular carcinoma patients after thermal ablation

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BCL6B methylation is associated with poor prognosis in patients with hepatocellular carcinoma after thermal ablation

OS is the final aim for all treatments in HCC. Verifying whether BCL6B methylation is an independent risk factor for survival following thermal ablation in HCC using univariate analysis revealed that BCL6B methylation, AST, GGT ALB, and HG were predictive factors for survival (P = 0.028, 0.004, 0.005, 0.043 and 0.029, respectively) [Table 4]. Multivariate analysis revealed that no index was a significant predictive factor (P > 0.050) [Table 4]. Furthermore, unconditional logistic regression was performed by progressively adjusting for clinicopathologic characteristics by stratified analysis, AST, ALT, AFP, and Child–Pugh were also not significant predictive factors (P > 0.05) [Table 5]. Thus, BCL6B methylation was a risk factor for survival in HCC after thermal ablation, but not an independent one.
Table 4: Univariate and multivariate analysis of variables for overall survival in early-stage hepatocellular carcinoma patients after thermal ablation

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Table 5: Association of BCL6B methylation with overall survival in early-stage hepatocellular carcinoma patients after thermal ablation

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 > Discussion Top


DNA methylation is the main epigenetic feature of mammalian DNA involved in cancer development and progression through the transcriptional regulation of gene expression.[25],[26] Aberrant DNA methylation is a universal finding in cancer, associated with the silencing of TSGs by gene-specific hypermethylation.[27],[28] DNA methylation profiling offers several advantages over somatic mutation analysis for cancer detection, including higher clinical sensitivity and dynamic range.[29] Furthermore, aberrant DNA methylation can be reversed by methyltransferase inhibitors, which can be used in the clinic easily.[11] Therefore, efficient detection of DNA methylation markers for HCC diagnosis and prognosis prediction would provide the foundation for epigenetic therapy. BCL6B methylation is a frequent event in HCC and is associated with hepatitis B infection.[16]

In this study, among the 23 indexes, the levels of ALB, CHE, and ACL in the BCL6B unmethylated group were higher than those in the BCL6B methylated group. ALB and CHE reflected liver cell synthesis and reserve function, which is associated with hepatitis infection. ACL reflects the anti-tumor immunity ability of patients and has been reported as an independent factor for recurrence, metastasis, and survival after treatment.[30] All results suggested that BCL6B methylation is an important factor in HCC development and progression, especially mediating the anti-tumor capacity of lymphocytes. Takamori et al. reported that BCL6B is necessary for the activation of naive T cells to antigenic stimulation.[31] In 2005, Manders et al. reported that BCL6B mediated the enhanced magnitude of the secondary response of memory CD8+ T lymphocytes.[32] Cai et al. reported that the epigenetic inactivation of BCL6B promoted gastric cancer through the amplification of the gastric inflammatory response in vivo and offered a new approach for treatment and regenerative medicine in 2019, indicating that BCL6B methylation mediated the tumor immune microenvironment.[33] Thus, BCL6B might be involved in mediating the immune microenvironment in HCC. However, the regulatory mechanisms warrant further study.

The relationship between BCL6B methylation and prognosis during follow-up was evaluated. The results showed that 1-, 3-, and 5-year metastasis and OS rates in the BCL6B methylated group were higher than those in the unmethylated group. Thus, BCL6B methylation is a valuable prognostic factor for patients with HCC after thermal ablation. Furthermore, Kaplan–Meier analysis results revealed that BCL6B methylation in HCC with higher metastasis and low survival rates with significant difference compared with that of the BCL6B unmethylated group. This phenomenon can be explained by the results of Wang et al., who reported that BCL6B functions as a tumor suppressor to inhibit HCC metastases by upregulating E-cadherin, OB-cadherin and VEGFA in vitro, and further verified by lung metastasis in an orthotopic HCC mouse model in vivo.[18] Thus, BCL6B is associated with poor prognosis by promoting metastasis in HCC.

The management of HCC requires a multidisciplinary approach for its heterogeneity. Thermal ablation, a promising technique, is mainly used for diameters <5 cm in HCC.[19] In this study, we verified whether BCL6B methylation was an independent factor for prognosis after thermal ablation. Univariate and multivariate analyses revealed that BCL6B methylation was a risk factor for metastasis. However, age, virus load, AST, and CHE were risk factors too. Tumor size, number, hepatitis type, differentiation degree, Child–Pugh stratification, pre-ablation AFP level, PT, WBC, CHE, ACL, and liver cirrhosis were reported as possible factors related to HCC prognosis after ablation.[6],[34],[35] For eliminating the confounding effects of other factors, multivariate Cox regression analysis was performed by progressively adjusted stratified analysis. Adjustment analysis indicated that no significant difference was detected among ORs for BCL6B methylation predicating metastasis. The results indicated that BCL6B methylation was an independent risk factor for metastasis. For the OS, only univariate analysis indicated that BCL6B methylation was a risk factor. However, the same conclusion was not reached using multivariate Cox regression analysis and adjustment analysis. The results indicated that liver function is also an important factor for long time prognosis. All results suggested that in addition to liver function, metastasis was an important risk factor for poor prognosis. Therefore, to achieve a promising prognosis for HCC, preventing tumor metastasis and protecting liver function are equally important. A comprehensive treatment strategy is a rational approach. Some success has been achieved in treating solid malignancies using low-dose epigenetic-modulating agents.[36] By defining methylation silenced biomarker related to HCC prognosis after ablation, our results may help identify patients who would benefit from a combination of ablation and epigenetic therapy.

Our study has several limitations, in addition to its retrospective nature. Although the follow-up period was longer than 5 years, the sample size was small and the participants in the two groups were not matched. Hypermethylation of BCL6B is a frequent event in patients with HCC.[16] A larger sample may provide more convincing results. Moreover, the molecular regulatory mechanisms of the epigenetic silencing of BCL6B, resulting in poor prognosis and in promoting metastasis in HCC, need to be clarified. Thereafter, more efficient treatments can be developed. Last, the immune microenvironment in HCC influence its prognosis; the regulatory mechanism of BCL6B methylation mediating the immune status warrants further study.[37]

In summary, BCL6B methylation, as a valuable new prognostic factor, was found to be associated with higher metastasis and poorer prognosis in early-stage HCC after thermal ablation, and it was an independent risk factor for metastasis. To some extent, BCL6B methylation correlates with poor prognosis by promoting metastasis. Our results provide a foundation for combined ablation and epigenetic therapy for patients with HCC in the future.

Acknowledgment

This work was supported by the National Key R&D Program of China (No. 2017YFC0112000), three grants 81430039, 81627803 and 81801723 from the National Scientific Foundation Committee of China.

Financial support and sponsorship

This work was supported by the National Key R&D Program of China (No. 2017YFC0112000), three grants 81430039, 81627803 and 81801723 from the National Scientific Foundation Committee of China.

Conflicts of interest

There are no conflicts of interest.



 
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