Fengping Huang

Polymorphisms of LIG4 and XRCC4 Involved in the NHEJ Pathway Interact to Modify Risk of Glioma

Although the role of environmental risk factors in the etiology of gliomas remains to be elucidated, accumulative epidemiological evidence suggests that genetic factors, such as variants in genes involved in DNA repair, may also play an important role. LIG4 and XRCC4 are known to form a complex and are functionally linked in the repair of double‐stranded DNA breaks. To determine whether LIG4 and XRCC4 polymorphisms are associated with susceptibility to glioma and whether there are interactions between LIG4 and XRCC4, we conducted a case–control study of 771 glioma patients and 752 cancer‐free controls, assessed the associations between glioma risk and 20 tagging SNPs, and evaluated their potential gene–gene interactions using the multifactor dimensionality reduction (MDR), interaction dendrogram, and entropy analysis. In the single‐locus analysis, only one variant, the LIG4 SNP2 rs3093739:T>C (P‐permutation=0.009) was significantly associated with risk of developing glioma. Haplotype analysis revealed an association of glioma risk with genetic variants in LIG4 block 1 (global P=0.011), and XRCC4 blocks 2 and 4 (both global P<0.0001). Moreover, the MDR analysis suggested a significant three‐locus interaction model involving LIG4 SNP4 rs1805388:C>T, XRCC4 SNP12 rs7734849:A>T, and SNP15 rs1056503:G>T. Further dendrogram and graph analysis indicated a more‐than‐additive effect among these three loci. These results suggested that these variants may contribute to glioma susceptibility. Hum Mutat 29(3), 381–389, 2008.

XRCC3 haplotypes and risk of gliomas in a Chinese population: A hospital-based case-control study

In mammalian cells, X‐ray repair cross‐complementing group3 (XRCC3) plays an important role in the DNA double‐strand breaks (DSBs) repair by homologous recombination. Genetic polymorphisms in the XRCC3 gene may potentially affect the repair of DSBs and thus confer susceptibility to gliomas. In this study, we used a haplotype‐based approach to investigate whether 4 tagging single nucleotide polymorphisms of the XRCC3 gene are associated with risk of gliomas in 771 glioma patients and 752 cancer‐free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the unconditional logistic regression, and haplotype associations were estimated using Haplo.Stat. After adjustment for age and sex, the variant G allele of rs861530 and T allele of rs3212092 were significantly associated with an increased risk of gliomas (AG/GG versus AA: adjusted OR = 1.44, 95% CI = 1.15–1.80, p = 0.001 and CT/TT versus CC: adjusted OR = 1.66, 95% CI = 1.12–2.46, p = 0.013, respectively). Consistent with these results, XRCC3 haplotype “GGCC” containing rs861530 G allele and haplotype “AGTC” containing rs3212092 T allele were also significantly associated with an elevated risk of gliomas compared with the common haplotype “AGCC” (adjusted OR = 1.35, 95% CI = 1.14–1.58, p = 0.000 and adjusted OR = 1.67, 95% CI = 1.11–2.52, p = 0.015, respectively). Our results suggest that common genetic variants in the XRCC3 gene may modulate glioma risk.

The relationship between Cho/NAA and glioma metabolism: implementation for margin delineation of cerebral gliomas

BackgroundThe marginal delineation of gliomas cannot be defined by conventional imaging due to their infiltrative growth pattern. Here we investigate the relationship between changes in glioma metabolism by proton magnetic resonance spectroscopic imaging (1H-MRSI) and histopathological findings in order to determine an optimal threshold value of choline/N-acetyl-aspartate (Cho/NAA) that can be used to define the extent of glioma spread.MethodEighteen patients with different grades of glioma were examined using 1H-MRSI. Needle biopsies were performed under the guidance of neuronavigation prior to craniotomy. Intraoperative magnetic resonance imaging (MRI) was performed to evaluate the accuracy of sampling. Haematoxylin and eosin, and immunohistochemical staining with IDH1, MIB-1, p53, CD34 and glial fibrillary acidic protein (GFAP) antibodies were performed on all samples. Logistic regression analysis was used to determine the relationship between Cho/NAA and MIB-1, p53, CD34, and the degree of tumour infiltration. The clinical threshold ratio distinguishing tumour tissue in high-grade (grades III and IV) glioma (HGG) and low-grade (grade II) glioma (LGG) was calculated.ResultsIn HGG, higher Cho/NAA ratios were associated with a greater probability of higher MIB-1 counts, stronger CD34 expression, and tumour infiltration. Ratio threshold values of 0.5, 1.0, 1.5 and 2.0 appeared to predict the specimens containing the tumour with respective probabilities of 0.38, 0.60, 0.79, 0.90 in HGG and 0.16, 0.39, 0.67, 0.87 in LGG.ConclusionsHGG and LGG exhibit different spectroscopic patterns. Using 1H-MRSI to guide the extent of resection has the potential to improve the clinical outcome of glioma surgery.

Cationic core–shell nanoparticles with carmustine contained within O6-benzylguanine shell for glioma therapy

The application of carmustine (BCNU) for glioma treatment is limited due to its poor selectivity for tumor and tumor resistance caused by O⁶-methylguanine-DNA-methyl transferase (MGMT). To improve the efficacy of BCNU, we constructed chitosan surface-modified poly (lactide-co-glycolides) nanoparticles (PLGA/CS NPs) for targeting glioma, loading BCNU along with O⁶-benzylguanine (BG), which could directly deplete MGMT. With core-shell structure, PLGA/CS NPs in the diameter around 177 nm showed positive zeta potential. In vitro plasma stability of BCNU in NPs was improved compared with free BCNU. The cellular uptake of NPs increased with surface modification of CS and decreasing particle size. The cytotoxicity of BCNU against glioblastoma cells was enhanced after being encapsulated into NPs; furthermore, with the co-encapsulation of BCNU and BG into NPs, BCNU + BG PLGA/CS NPs showed the strongest inhibiting ability. Compared to free drugs, PLGA/CS NPs could prolong circulation time and enhance accumulation in tumor and brain. Among all treatment groups, F98 glioma-bearing rats treated with BCNU + BG PLGA/CS NPs showed the longest survival time and the smallest tumor size. The studies suggested that the co-encapsulation of BCNU and BG into PLGA/CS NPs could remarkably enhance the efficacy of BCNU, accompanied with greater convenience for therapy.

Possible association between polymorphisms of human vascular endothelial growth factor A gene and susceptibility to glioma in a Chinese population

Vascular endothelial growth factor A (VEGFA), one of the most predominant mediators of pathologic angiogenesis, plays a critical role in glioma carcinogenesis and development via promoting tumor growth. We hypothesized that VEGFA polymorphisms may influence glioma risk. We recently genotyped 9 VEGFA single‐nucleotide polymorphisms (SNPs) in 766 glioma patients and 824 cancer‐free controls selected from a Chinese population. We evaluated the glioma risk conferred by individual SNPs, haplotypes as well as cumulative SNP effect. In the single‐locus analysis, we found that rs2010963 (G+405C, G‐634C) [odds ratio (OR) = 1.29; 95% confidence interval (CI) = 1.04–1.58; GC/CC vs. GG] and rs3025030 (OR = 2.21; 95% CI = 1.18–4.14; CC vs. GG/GC) were associated with increased risk for glioma, and rs3024994 (OR = 0.66; 95% CI = 0.47–0.94; CT/TT vs. CC) was associated with reduced glioma risk, albeit insignificant after Bonferroni correction for multiple comparisons. The haplotype‐based analysis revealed that AGG in block 1 and ATT, ACT in block 2 were associated with 20–40% reductions in glioma risk. The inverse association of haplotype AGG containing rs2010963G remained significant after correction for multiple testing (p = 0.002, pcorrected = 0.022). The aforementioned 3 SNPs revealed a significant cumulative risk effect; the increased risk for glioma was 1.38‐fold for each additional adverse genotype he or she carries (ptrend = 8.4 × 10−5). Our findings suggested that VEGFA variants may be involved in glioma risk. Larger studies with ethnically diverse populations are warranted to confirm the results reported in this investigation.

Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle: Case report and review of literature

Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle has been identified as a novel and distinctive type of primary central nervous system neoplasm. In this report, we present a case with RGNT arising from the right cerebellar hemisphere. A 30-year-old female patient complained of headache for a five-year duration. Preoperative MRI revealed a well-circumscribed, cystic-solid lesion with hypo-intensity on T1-weighted image, hyper-intensity on T2-weighted image, and significant dot-like enhancement after IV contrast. Gross total resection was achieved in this case via suboccipital retro-sigmoidal approach, and RGNT was confirmed in the final histopathological diagnosis. RGNT of the fourth ventricle is a rare, benign tumor with an excellent prognosis. Operation is recommended as the prior protocol of treatment, and the follow-up MRI is necessary to evaluate the long-term prognostic effects. Currently, only one case of progression or recurrence has been reported in the postoperative course.

Serum GFAP autoantibody as an ELISA-detectable glioma marker

Glioma is the most common primary brain tumor, yet the high cost of diagnostic imaging has made early detection of asymptomatic glioma a formidable challenge. Thus, the development of a convenient, sensitive, and cost-effective diagnostic strategy, such as enzyme-linked immunosorbent assay (ELISA) based on glioma-specific and World Health Organization (WHO) grade-specific autoantibody serum markers, is necessary. To this end, a comparative proteomic analysis based on two-dimensional western blotting was carried out with the sera of glioma patients and normal controls. Of the 11 novel glioma-expressed autoantibodies, the autoantibody against glial fibrillary acidic protein (GFAP) showed the highest differential expression. To investigate the potential clinical utility of the GFAP autoantibody as an early diagnostic marker for glioma, an ELISA-based assay was developed and validated with sera from glioma patients with WHO grades II (n = 19), III (n = 17), and IV (n = 24). The GFAP autoantibody level directly correlated with WHO grade and tumor volume. Sera from patients of non-glioma brain tumors, as well as non-brain tumors, showed much lower levels of GFAP autoantibody than those of the glioma patients, indicating that elevated GFAP autoantibody is specific to glioma patients. Analysis of the receiver operating characteristics curve suggested that the new ELISA has good distinguishing power and sensitivity for diagnosing glioma patients. This is the first ELISA assay developed for an autoantibody of a glioma antigen and may prove valuable for the clinical detection of glioma.

SPP1 promoter polymorphisms and glioma risk in a Chinese Han population

SPP1 was found to be significantly upregulated in many kinds of malignant tumors, including gliomas. Considering that gene polymorphisms have been implicated in the development of gliomas, we performed an association study between SPP1 functional promoter region polymorphisms and glioma risk in a Chinese population. We found significant evidence of an association between SPP1 promoter polymorphisms and glioma risk. For the −155_156insG variant, the −155_156GG allele was found to be significantly associated with an increased risk of glioma (P=0.020, odds ratio (OR)=1.202, 95% confidence interval (CI): 1.028–1.408). Individuals with the genotype containing the GG allele had a 1.372-fold increased risk (P=0.006, OR=1.372, 95% CI: 1.095–1.719). Further stratified analyses suggested that a significant association existed in adult glioma patients, male subjects and in cases without a family history of cancer. Alternatively, the study of single-nucleotide polymorphism −443C/T in a recessive model revealed that the genotype CC + CT significantly decreased the risk of glioma when compared with TT (P=0.023, OR=0.774, 95% CI: 0.621–0.966). After the analysis of haplotypes, the haplotype −155_156GG/−443T was represented at a significantly higher frequency in cases (P=0.029, OR=1.192, 95% CI: 1.018–1.395). Cellular assay indicated that the transcriptional activity of the SPP1 promoter containing the −155_156GG allele significantly increased in glioma cells. Thus, variants of the SPP1 promoter might influence the risk of glioma by regulating promoter activity. Further analyses are necessary to validate our observation in larger samples or in other ethnic groups.

TMZ-induced PrPc/par-4 interaction promotes the survival of human glioma cells

Malignant gliomas recur even after extensive surgery and chemo‐radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ), has demonstrated promising activity against gliomas, the effects last only a few months and drug resistance develops thereafter in many cases. It has been acknowledged that glioma cells respond to TMZ treatment by undergoing G2/M arrest, but not apoptosis. Here we demonstrate a phase‐specific chemotherapy resistance due to cellular prion protein (PrPc) in human glioma cells upon TMZ treatment. TMZ‐induced G2/M‐arrested cultures show an upregulation of PrPc expression and are more resistant, whereas G1/S‐phase cells that show decreased levels of PrPc are more sensitive to apoptosis. Furthermore, an investigation into the biological significance of PrPc association with par‐4 provided the first evidence of a relationship between the endogenous levels of PrPc and the resistance of glioma cells to the apoptotic effects of TMZ. Upon TMZ treatment, PrPc exerts its antiapoptotic activity by inhibiting PKA‐mediated par‐4 phosphorylation that are important for par‐4 activation, nuclear entry and initiation of apoptosis. In context with cell cycle‐dependent responses to chemotherapy, the data from this study suggest the possibility of exploiting the PrPc‐dependent pathway to improve the efficacy of TMZ‐based regimen for patients with gliomas.

Clinicopathological analysis of rhabdoid meningiomas: report of 12 cases and a systematic review of the literature.

BACKGROUND Rhabdoid meningioma (RM) is a rare subtype of meningioma, classified as World Health Organization grade III with a poor prognosis. Here we present our experience on RM and review relevant literature in an attempt to investigate the clinical features, treatment, and prognosis of these tumors. METHODS Twelve patients underwent surgical treatment for intracranial RMs between 2003 and 2008 in our department. The clinical data, radiological manifestations, pathological findings, treatments, and prognoses of the patients were analyzed retrospectively; 58 other cases reported previously by other institutions also were summarized and reviewed. RESULTS These cases (6 men and 6 women, mean age 44.3 years old, ranging from 21 to 78 years old) constituted 0.28% of all meningioma patients admitted at our department during the same period. The mean duration of symptoms was relatively short at 1.6 months. There was no significant clinical manifestation noted, and the radiologic findings fell into 3 types of images. In the follow-up period of over 30 months, 7 patients died; 5 patients had recurrence and 2 patients died of unknown causes. CONCLUSIONS RM is a rare subtype of malignant meningioma featuring an increased tendency for recurrence and possible metastasis. It is still difficult to make a correct preoperative diagnosis. The overall prognosis for these patients is extremely poor, and the role of various adjuvant treatments needs to be further studied.