Functional BCL-2 rs2279115 Promoter Noncoding Variant Contributes to Glioma Predisposition,Especially in Males

Abstract

As a crucial oncogene, B cell lymphoma-2 (BCL-2) could promote cancer cell survival by inhibiting apoptosis via suppressing activation of proapoptotic proteins, such as BAX and BAK. There is a functional rs2279115 genetic polymorphism locating in BCL-2 promoter and deregulating BCL-2 expression. However, it is still largely undefined how BCL-2 rs2279115 promoter noncoding genetic variant is involved in glioma development. We examined the association between BCL-2 rs2279115 and glioma risk using a case–control approach. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression adjusted by age and sex. Our results demonstrated that BCL-2 rs2279115 was significantly associated with glioma risk. The odd of individuals harboring A allele (CA + AA genotype) was 0.50 (95% CI = 0.39–0.64, p = 1.0 × 10⁻⁷) compared with CC genotype carriers. Stratification analyses by sex elucidated that BCL-2 rs2279115 was significantly associated with glioma risk in males (OR = 0.41, 95% CI = 0.30–0.58, p = 1.0 × 10⁻⁷), but not in females (p > 0.05). In summary, our results indicate that the functional BCL-2 rs2279115 genetic variant contributes to glioma predisposition and suggest prevalent involvement of regulatory genetic variations in glioma development.

Introduction

Glioma is the most common and highly aggressive malignant brain tumor in the world (Maher et al., 2001). Glioma accounts for 70% of adult primary malignant brain tumors (Goodenberger and Jenkins, 2012). Despite all efforts of surgery in combination with chemo- and/or radiotherapy, gliomas are still incurable. Glioma is currently classified as ependymomas, astrocytomas, oligodendrogliomas, brain stem gliomas, or mixed gliomas, such as oligoastrocytomas (Omuro and DeAngelis, 2013). The prognosis of glioma remains depressing with a 5-year survival rate for glioblastoma of ∼5% and a survival rate varies according to multiple factors. Several genome-wide association studies or meta-analyses identified a number of novel genetic variations associated with risk of glioma among different ethnic populations (Shete et al., 2009; Rajaraman et al., 2012; Kinnersley et al., 2015; Melin et al., 2017), indicating that genetic makeup may also contribute to glioma susceptibility.

Apoptosis, also known as programmed cell death, was found in almost all organisms (Ashkenazi and Dixit, 1998). Considered a crucial component of various biological processes, apoptosis is commonly characterized by diverse morphological changes and energy-dependent biochemical mechanisms (Elmore, 2007; Taylor et al., 2008; Ichim and Tait, 2016; Strzyz, 2017). Inappropriate apoptosis is vital in many human conditions, including cancers (Elmore, 2007; Ouyang et al., 2012). Apoptosis is preciously regulated by many genes, including multiple oncogenes and tumor suppressor genes (Danial and Korsmeyer, 2004). For example, B cell lymphoma-2 (BCL-2) family proteins that consist of both pro- and antiapoptotic members are essential regulators of apoptosis (Kelly and Strasser, 2011). All BCL-2 family proteins share sequence homology in their BCL-2 homology domains and may be promising drug targets of cancer therapy (Ashkenazi et al., 2017).

Localized to the outer membrane of mitochondria, BCL-2 plays an important part in promoting cellular survival and inhibiting the actions of proapoptotic proteins such as BAX and BAK (Hardwick and Soane, 2013). Therefore, BCL-2 serves as an oncogene in several cancers (Hockenbery, 1994; Adams and Cory, 2007; Yip and Reed, 2008; Kelly and Strasser, 2011), and its expression is significantly associated with cancer progression and sensitivity of chemotherapeutic drugs as well as radiation therapy (Mirkovic et al., 1997; Pardo et al., 2002; Loriot et al., 2014). There is a functional rs2279115 genetic polymorphism located in the inhibitory promoter of BCL-2 (Park et al., 2004; Chen et al., 2007) and has been found to contribute to susceptibility of esophageal squamous cell carcinoma (ESCC) and small lung cancer (SCLC) (Pan et al., 2015; Yang et al., 2016). Considering the importance of BCL-2 rs2279115 in tumorgenesis, we hypothesized that the BCL-2 rs2279115 might also contribute to glioma development. To verify this hypothesis, we conducted a case–control study and found that BCL-2 rs2279115 was significantly associated with glioma risk in a Chinese Han population.

Materials and Methods

Study subjects

There are a total of 404 glioma patients and 820 healthy controls enrolled in this study, which has been reported previously (Chen et al., 2014). In brief, glioma patients were newly diagnosed and histologically confirmed. All patients were recruited from June 2010 to July 2013 at Beijing Shijitan Hospital, Capital Medical University (Beijing). The histopathological type of tumors was classified based on 2007 WHO classification of tumor of the central nervous system (Lu et al., 2014). The controls were cancer-free individuals during the same time period as the cases were collected and were frequency-matched to glioma patients based on sex and age (±5 years) (Supplementary Table S1; Supplementary Data are available online at www.liebertpub.com/dna). At recruitment, informed consent was obtained from each subject. This study was approved by the Institutional Review Boards of Shandong Cancer Hospital (protocol no.: 201605005).

Genotyping of BCL-2 rs2279115 polymorphism

BCL-2 rs2279115 was genotyped using the MassARRAY system (Sequenom, Inc., San Diego, CA) as reported previously (Pan et al., 2015; Yang et al., 2016). In brief, BCL-2 rs2279115 PCR primers are 5′-ACGTTGGATGTGAATCTCTATCCACGGGAC-3′ (Forward) and 5′-ACGTTGGATGAAGAGGATTCCTGCCTCCGT-3′ (Reverse). BCL-2 rs2279115 UEP_SEQ primer is 5′-AGGCGAGAGACAGGGGAGA-3′. BCL-2 rs2279115 EXT1_SEQ primer is 5′-AGGCGAGAGACAGGGGAGAG-3′. BCL-2 rs2279115 EXT2_SEQ primer is 5′-AGGCGAGAGACAGGGGAGAT-3′. A 15% blind, random sample of study subjects was genotyped in duplicates, and the reproducibility was 100%.

BCL-2 reporter gene constructs

Specific primer pairs (Supplementary Table S2) with XhoI and KpnI restriction sites were used to amplify a 194 nt DNA fragments spanning 5′-region of BCL-2 from human genomic DNA carrying BCL-2 rs2279115 CC or rs2279115 AA genotype. The PCR products were then digested with XhoI and KpnI (TaKaRa) and ligated into an appropriately digested pGL3-Basic vector (Promega) containing the firefly luciferase gene as a reporter. The resultant plasmid designated pBCL-C or pBCL-A. Complete DNA sequencing confirmed the orientation and integrity of these two reporter constructs.

Dual-luciferase reporter assays

Both U251 and LN18 glioma cells were transfected with various reporter constructs (pGL3-Basic, pBCL-C, or pBCL-A) and pRL-SV40 (Luciferase Assay System; Promega). Dual-luciferase activities were examined at 48 h after transfection. For each reporter construct, three independent transfections were done, and each was performed in triplicate.

Statistics

The differences of demographic variables and genotype distributions of BCL-2 rs2279115 between cases and controls were analyzed using Pearson's χ² test. The associations between genotypes of the BCL-2 rs2279115 SNP and glioma risk were calculated by ORs and their 95% confidence intervals (CIs) computed by logistic regression models. All ORs were adjusted for age and sex, where it was appropriate. A p-value of less than 0.05 was considered as statistical significance, and all statistical tests were two-sided. All statistical analyses were performed using SPSS 20.0 (SPSS, Inc.).

Results

No statistically significant differences were observed between glioma patients and healthy controls in terms of median age and sex distribution (p > 0.05), suggesting that the frequency matching was appropriate (Supplementary Table S1). Genotype frequencies of BCL-2 rs2279115 genetic variant are summarized in Table 1. All observed genotype frequencies in both patients and controls conformed to Hardy–Weinberg equilibrium. To examine the role of BCL-2 rs2279115 in glioma development, unconditional logistic regression analysis was performed, adjusted by age and sex. The BCL-2 rs2279115 C allele was a protective factor for glioma. In details, the rs2279115 CA genotype was significantly associated with decreased glioma risk (odds ratio [OR] = 0.53, 95% CI = 0.41–0.69, p = 2.0 × 10⁻⁶) compared with the CC genotype. Similarly, carriers of the rs2279115 AA genotype showed a 0.42-fold decreased glioma risk compared with individuals with the CC genotype (95% CI = 0.29–0.61, p = 5.0 × 10⁻⁶). In the pooled analyses, significantly reduced glioma risk was observed among CA and AA carriers compared to individuals with CC rs2279115 genotype (OR = 0.50, 95% CI = 0.39–0.64, p = 1.0 × 10⁻⁷) (Table 1 and Supplementary Fig. S1).

Table 1.

Associations Between BCL- 2 rs2279115 Genetic Variant and Glioma Risk

			Glioma risk ^a
Genotypes	Cases, no. (%)	Controls, no. (%)	OR (95% CI)	p
rs2279115	404	820
CC	177 (43.81)	230 (28.05)	Reference
CA	176 (43.56)	433 (52.80)	0.53 (0.41–0.69)	2.0 × 10⁻⁶
AA	51 (12.62)	157 (19.15)	0.42 (0.29–0.61)	5.0 × 10⁻⁶
CA + AA	227 (56.19)	590 (71.95)	0.50 (0.39–0.64)	1.0 × 10⁻⁷

OR calculated by logistic regression.

CI, confidence interval; OR, odds ratio.

We further investigated the glioma risk associated with the BCL-2 rs2279115 genotypes by stratifying for age, sex, disease stage, and pathological subtypes. In stratified analyses with age, rs2279115 CA or AA genotype was significantly associated with decreased risk in subjects aged 57 years or younger (OR = 0.58, 95% CI = 0.40–0.84, p = 0.004 for CA genotype; OR = 0.49, 95% CI = 0.29–0.84, p = 0.010 for AA genotype). Similarly, carriers of the rs2279115 CA or AA genotype showed significantly and consistently decreased risk to develop glioma compared with CC genotype carriers (OR = 0.50, 95% CI = 0.34–0.74, p = 4.8 × 10⁻⁴ for CA genotype; OR = 0.38, 95% CI = 0.22–0.66, p = 0.010 for AA genotype; Table 2).

Table 2.

Risk of Glioma Associated with BCL-2 rs2279115 Genetic Variant Stratified by Age

				Glioma risk ^a
Age	Genotypes	Cases, no. (%)	Controls, no. (%)	OR (95% CI)	p
≤41	rs2279115	205	437
	CC	88 (42.93)	125 (28.60)	Reference
	CA	92 (44.88)	234 (53.55)	0.58 (0.40–0.84)	0.004
	AA	25 (12.20)	78 (17.85)	0.49 (0.29–0.84)	0.010
>41	rs2279115	199	383
	CC	89 (44.72)	105 (27.42)	Reference
	CA	84 (42.21)	199 (51.96)	0.50 (0.34–0.74)	4.8 × 10⁻⁴
	AA	26 (13.07)	79 (20.63)	0.38 (0.22–0.66)	0.001

Data were calculated by logistic regression adjusted for sex.

Compared with the rs2279115 CC genotype, a significantly decreased glioma risk was associated with CA or AA genotypes for male (OR = 0.47, 95% CI = 0.33–0.68, p = 2.4 × 10⁻⁵ for CA genotype; OR = 0.27, 95% CI = 0.16–0.46, p = 2.0 × 10⁻⁶ for AA genotype) (Table 3 and Supplementary Fig. S1). However, no such associations were observed in females (all p > 0.05). These results suggested that BCL-2 rs2279115 polymorphism might be a male-specific genetic component for glioma risk.

Table 3.

Risk of Glioma Associated with BCL-2 rs2279115 Genetic Variant Stratified by Sex

				Glioma risk ^a
Sex	Genotypes	Cases, no. (%)	Controls, no. (%)	OR (95% CI)	p
Male	rs2279115	237	456
	CC	113 (47.68)	124 (27.19)	Reference
	CA	102 (43.04)	239 (52.41)	0.47 (0.33–0.68)	2.4 × 10⁻⁵
	AA	22 (9.28)	93 (20.39)	0.27 (0.16–0.46)	2.0 × 10⁻⁶
Female	rs2279115	167	364
	CC	64 (38.32)	106 (29.12)	Reference
	CA	74 (44.31)	194 (53.30)	0.66 (0.43–1.02)	0.063
	AA	29 (17.37)	64 (17.58)	0.39 (0.45–1.38)	0.393

Data were calculated by logistic regression adjusted for age.

In stratified analyses with grade, significantly decreased glioma risk was found in carriers of the BCL-2 rs2279115 CA or AA genotype among patients with grade 1 or 2 disease (OR = 0.51, 95% CI = 0.36–0.71, p = 6.2 × 10⁻⁵ for CA genotype; OR = 0.43, 95% CI = 0.27–0.70, p = 0.001 for AA genotype). Similar results were found for patients with grade 3 or 4 disease (OR = 0.55, 95% CI = 0.39–0.77, p = 0.001 for CA genotype; OR = 0.41, 95% CI = 0.25–0.67, p = 4.4 × 10⁻⁴ for AA genotype) (Table 4 and Supplementary Fig. S1).

Table 4.

Risk of Glioma Associated with BCL-2 rs2279115 Genetic Variant Stratified by Grade

			Glioma risk ^a
Grade	Genotypes	Cases, no. (%)	OR (95% CI)	p
1 + 2	rs2279115	208
	CC	93 (44.71)	Reference
	CA	88 (42.31)	0.51 (0.36–0.71)	6.2 × 10⁻⁵
	AA	27 (12.98)	0.43 (0.27–0.70)	0.001
3 + 4	rs2279115	195
	CC	84 (43.08)	Reference
	CA	87 (44.62)	0.55 (0.39–0.77)	0.001
	AA	24 (12.31)	0.41 (0.25–0.67)	4.4 × 10⁻⁴

Data were calculated by logistic regression, adjusted for sex and age.

We also examined the impacts of the BCL-2 rs2279115 genetic variant on risk of different histopathological tumors. As shown in Table 5 and Supplementary Figure S1, we found that the rs2279115 CA or AA genotype carriers had a decreased risk, 0.62 times or 0.49 times, to develop astrocytic tumors compared with the CC genotype carriers (95% CI = 0.44–0.86, p = 0.005 or 95% CI = 0.31–0.79, p = 0.003) (Table 5). However, BCL-2 rs2279115 was not associated with risk of oligodendroglial tumors (OR = 0.39, 95% CI = 0.25–0.61, p = 0.070 for CA genotype) compared to the CC genotype (Table 5). We did not examine the association between the AA genotype and glioma risk since there were only three cases with oligodendroglial tumors. On the contrary, BCL-2 rs2279115 polymorphism was significantly associated with reduced risk of both oligoastrocytic tumors and ependymal tumors (all p < 0.05).

Table 5.

Risk of Glioma Associated with BCL-2 rs2279115 Genetic Variant Stratified by Subtypes

			Glioma risk ^a
Subtypes	Genotypes	Cases, no. (%)	OR (95% CI)	p
Astrocytic tumors	rs2279115	207
	CC	83 (40.10)	Reference
	CA	96 (46.38)	0.62 (0.44–0.86)	0.005
	AA	28 (13.53)	0.49 (0.31–0.79)	0.003
Oligodendroglial tumors	rs2279115	37
	CC	17 (45.95)	Reference
	CA	17 (45.95)	0.53 (0.26–1.05)	0.070
	AA	3 (8.11)	NC	NC
Oligoastrocytic tumors	rs2279115	105
	CC	52 (49.52)	Reference
	CA	38 (36.19)	0.39 (0.25–0.61)	3.5 × 10⁻⁵
	AA	15 (14.29)	0.42 (0.23–0.77)	0.005
Ependymal tumors	rs2279115	55
	CC	25 (45.45)	Reference
	CA	25 (45.45)	0.53 (0.30–0.94)	0.031
	AA	5 (9.09)	0.30 (0.11–0.79)	0.015

Data were calculated by logistic regression, adjusted for sex and age.

NC, not calculated.

Considering that the rs2279115 genetic variant is located in the P2 BCL-2 promoter, we detected the promoter activity of this region by two luciferase reporter constructs with different rs2279115 allele in U251 and LN18 glioma cells. Interestingly, the BCL-2 rs2279115C allelic reporter construct (pBCL-C) showed significantly higher luciferase activities compared with the rs2279115A allelic reporter construct (pBCL-A) in U251 cells (relative luciferase activity: 2.671 ± 0.835 vs. 1.697 ± 0.439) (p < 0.05). In addition, LN18 cells transfected with pBCL-C showed significantly higher luciferase activities compared with cells expressing pBCL-A (relative luciferase activity: 1.591 ± 0.226 vs. 1.083 ± 0.335) (p < 0.05).

Discussion

In the current study, we systematically investigated the association between BCL-2 rs2279115 and glioma susceptibility in a Chinese population. We found that BCL-2 rs2279115 C > A polymorphism was significantly associated with decreased glioma risk, with the A allele as the protective allele. Reporter gene assays indicated that the glioma susceptibility SNP rs2279115 at the P2 BCL-2 promoter has a genotype-specific effect on BCL-2 expression. Our data suggested that the functional BCL-2 rs2279115 SNP might contribute to glioma susceptibility.

As an important apoptosis inhibitor, BCL-2 serves as a critical oncogene during carcinogenesis. Its expression was positively correlated with cancer cell differentiation, but inversely associated with disease progression (Ohbu et al., 1997). There are two promoters for BCL-2, P1, and P2. BCL-2 is transcripted by the P1 promoter, while the P2 promoter acts as a negative regulatory element (Seto et al., 1988; Young and Korsmeyer, 1993). BCL-2 rs2279115 is a functional genetic variant located in the inhibitory P2 promoter (Park et al., 2004). Interestingly, the BCL-2 rs2279115 A allele might be inclined to render a better interaction with TP53, which will lead to a decrease in the BCL-2 expression eventually (Chen et al., 2007). BCL-2 rs2279115 polymorphism has been extensively studied in multiple cancer types. Our previous studies found that BCL-2 rs2279115 polymorphism contributes to ESCC and SCLC susceptibility in Chinese populations, and functional genetic variant could influence BCL-2 expression (Pan et al., 2015). In line with our current study, these previous data showed that BCL-2 rs2279115 A allele is protective allele for multiple cancers. However, Li et al. (2014) found that the BCL-2 rs2279115 polymorphism is associated with increased glioma risk in a southern Chinese population. However, this study recruited a relatively small sample size of glioma patients (248 glioma cases and 252 controls) to detect the moderate effect of this genetic polymorphism. In the present study with 404 GCA patients and 820 controls, we found that a significantly decreased glioma risk was associated with the rs2279115 A allele. There might be several limitations in this case–control study, that is, all glioma cases were recruited from the hospital, which may lead to inherent selection bias. As a result, our findings warrant to be validated in a population-based prospective study in the future. Secondly, given that many patients are scarce of molecular parameters in our study, we cannot perform histopathological stratification based on 2016 WHO classification of gliomas.

In conclusion, we provide evidences that that functional BCL-2 rs2279115 SNP is genetic susceptibility factors for development of glioma in a Chinese population, especially in males. This observational finding was validated with a series of reporter gene assays in both U251 and LN18 glioma cells. These findings support the hypothesis that the BCL-2 signaling pathway is involved in glioma development.

Footnotes

Acknowledgment

This study was partially supported by Capital Health Research Projects (2016-2-1073); National Natural Science Foundation of China (31671300, 31871306); and Taishan Scholars Program of Shandong Province (tsqn20161060).

Disclosure Statement

No competing financial interests exist.

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