PMC:6966482 / 10285-13871 JSONTXT

{"project":"2_test","denotations":[{"id":"31842352-26563502-17908813","span":{"begin":269,"end":271},"obj":"26563502"},{"id":"31842352-28578601-17908814","span":{"begin":499,"end":501},"obj":"28578601"},{"id":"31842352-30624711-17908815","span":{"begin":1144,"end":1146},"obj":"30624711"},{"id":"31842352-21946351-17908816","span":{"begin":1542,"end":1544},"obj":"21946351"},{"id":"31842352-25907361-17908817","span":{"begin":1545,"end":1547},"obj":"25907361"},{"id":"31842352-20455025-17908818","span":{"begin":1697,"end":1699},"obj":"20455025"},{"id":"31842352-29242642-17908819","span":{"begin":1700,"end":1702},"obj":"29242642"},{"id":"31842352-29242642-17908820","span":{"begin":1842,"end":1844},"obj":"29242642"},{"id":"31842352-22539396-17908821","span":{"begin":2101,"end":2103},"obj":"22539396"},{"id":"31842352-23535734-17908822","span":{"begin":2104,"end":2106},"obj":"23535734"},{"id":"31842352-30560391-17908823","span":{"begin":2193,"end":2195},"obj":"30560391"},{"id":"31842352-26646793-17908824","span":{"begin":2196,"end":2198},"obj":"26646793"},{"id":"31842352-30709929-17908825","span":{"begin":2542,"end":2544},"obj":"30709929"},{"id":"31842352-27780202-17908826","span":{"begin":3054,"end":3056},"obj":"27780202"},{"id":"31842352-23535731-17908827","span":{"begin":3057,"end":3059},"obj":"23535731"},{"id":"31842352-23535731-17908828","span":{"begin":3209,"end":3211},"obj":"23535731"},{"id":"31842352-26053551-17908829","span":{"begin":3212,"end":3214},"obj":"26053551"},{"id":"31842352-25027329-17908830","span":{"begin":3440,"end":3442},"obj":"25027329"}],"text":"3.1. All Glioma Risk Genes\nDefining the etiopathogenesis of different cancer types can be useful for several clinical applications. One example is to develop a biomarker panel for diagnostics of symptomatic patients as it has been successfully done in other diagnoses [12]. Increased basic knowledge of the mechanisms of glioma development could also help discover novel therapeutic targets, in analogy with how PARP inhibitors were discovered as a therapy in BRCA1 positive breast cancer patients [13]. For glioma, there is no robust blood test in diagnostics, even if some different pre-diagnostic biomarkers such as metabolites have been suggested [14]. Current therapeutic options have limited success and novel effective targeted treatments for glioma are urgently needed to improve survival.\nThe present study highlights a clear pattern of germline genetic variants associated with IDH-mutant and IDH-wildtype glioma, respectively (Figure 2). The variants with lowest frequency and strongest effect size are those most likely to be possible to incorporate in a clinical setting as it was shown in the recent study by Eckel-Passow et al. [10]. In the meta-analyses, we observe an association with all glioma for the TP53 gene variant and the TERT gene variant (Figure 1, group all, indicated in red). The TP53 variant is relatively rare, and its function is associated with both somatic loss of heterozygosity in the region and disrupted TP53 mRNA termination, as shown through previous studies of expression arrays in the TCGA dataset [15,16]. We did not find any differences in expression in the eQTL analyses (Table S3a). Furthermore, TP53 mutations are generally rare in glioma families [17,18]. TP53 is currently tested as a target for therapy, but as yet, no method has been introduced as a common treatment in any type of cancer [18].\nTERT encodes for telomerase reverse transcriptase, which has a function in telomere maintenance [19]. The TERT genetic risk variant has been associated with both glioma risk and telomere length indicating a functional effect through telomere regulation [20,21]. Longer leukocyte telomere length has been associated with increased risk of glioma [22,23]. The direct analyses of the single variant in TERT did not show any association with gene expression. However, recent transcriptome-wide association analysis (TWAS) using gene-based approaches that aggregate the effects of multiple variants suggests that the effect of TERT gene variants is mediated by transcription levels of the TERT gene [24]. The TWAS reported an association between genetically predicted TERT gene expression levels and risk of both GBM and non-GBM, which is in line with our finding that the TERT gene variant is associated with risk of glioma, regardless of IDH mutation status. One plausible mechanism of action for the TERT genetic variant is through methylation changes, considering that variants in the genomic area have been associated with lower methylation of a CpG site near the TERT transcription start site, cg23827991 [25,26]. Furthermore, the risk allele of rs10069690 has been shown to create an alternative splice donor site leading to a decrease in telomerase activity [26,27]. The genomic area is pleiotropic, and it is also possible that the variant exerts its function through a telomerase-independent pathway (alternative lengthening of telomeres) rather than by upregulating telomerase activity [28]. Several clinical trials that target TERT and telomere function are ongoing for different types of diseases but currently not for glioma [19]."}

{"project":"PubTator4TogoVar","denotations":[{"id":"13612","span":{"begin":3094,"end":3104},"obj":"SNP"}],"attributes":[{"id":"A13612","pred":"resolved_to","subj":"13612","obj":"tmVar:rs10069690;VariantGroup:12;CorrespondingGene:7015;RS#:10069690;CorrespondingSpecies:9606"}],"text":"3.1. All Glioma Risk Genes\nDefining the etiopathogenesis of different cancer types can be useful for several clinical applications. One example is to develop a biomarker panel for diagnostics of symptomatic patients as it has been successfully done in other diagnoses [12]. Increased basic knowledge of the mechanisms of glioma development could also help discover novel therapeutic targets, in analogy with how PARP inhibitors were discovered as a therapy in BRCA1 positive breast cancer patients [13]. For glioma, there is no robust blood test in diagnostics, even if some different pre-diagnostic biomarkers such as metabolites have been suggested [14]. Current therapeutic options have limited success and novel effective targeted treatments for glioma are urgently needed to improve survival.\nThe present study highlights a clear pattern of germline genetic variants associated with IDH-mutant and IDH-wildtype glioma, respectively (Figure 2). The variants with lowest frequency and strongest effect size are those most likely to be possible to incorporate in a clinical setting as it was shown in the recent study by Eckel-Passow et al. [10]. In the meta-analyses, we observe an association with all glioma for the TP53 gene variant and the TERT gene variant (Figure 1, group all, indicated in red). The TP53 variant is relatively rare, and its function is associated with both somatic loss of heterozygosity in the region and disrupted TP53 mRNA termination, as shown through previous studies of expression arrays in the TCGA dataset [15,16]. We did not find any differences in expression in the eQTL analyses (Table S3a). Furthermore, TP53 mutations are generally rare in glioma families [17,18]. TP53 is currently tested as a target for therapy, but as yet, no method has been introduced as a common treatment in any type of cancer [18].\nTERT encodes for telomerase reverse transcriptase, which has a function in telomere maintenance [19]. The TERT genetic risk variant has been associated with both glioma risk and telomere length indicating a functional effect through telomere regulation [20,21]. Longer leukocyte telomere length has been associated with increased risk of glioma [22,23]. The direct analyses of the single variant in TERT did not show any association with gene expression. However, recent transcriptome-wide association analysis (TWAS) using gene-based approaches that aggregate the effects of multiple variants suggests that the effect of TERT gene variants is mediated by transcription levels of the TERT gene [24]. The TWAS reported an association between genetically predicted TERT gene expression levels and risk of both GBM and non-GBM, which is in line with our finding that the TERT gene variant is associated with risk of glioma, regardless of IDH mutation status. One plausible mechanism of action for the TERT genetic variant is through methylation changes, considering that variants in the genomic area have been associated with lower methylation of a CpG site near the TERT transcription start site, cg23827991 [25,26]. Furthermore, the risk allele of rs10069690 has been shown to create an alternative splice donor site leading to a decrease in telomerase activity [26,27]. The genomic area is pleiotropic, and it is also possible that the variant exerts its function through a telomerase-independent pathway (alternative lengthening of telomeres) rather than by upregulating telomerase activity [28]. Several clinical trials that target TERT and telomere function are ongoing for different types of diseases but currently not for glioma [19]."}

{"project":"PubTatorOnTogoVar","denotations":[{"id":"13612","span":{"begin":3094,"end":3104},"obj":"SNP"},{"id":"T1","span":{"begin":3094,"end":3104},"obj":"SNP"}],"attributes":[{"id":"A13612","pred":"resolved_to","subj":"13612","obj":"tmVar:rs10069690;VariantGroup:12;CorrespondingGene:7015;RS#:10069690;CorrespondingSpecies:9606"}],"text":"3.1. All Glioma Risk Genes\nDefining the etiopathogenesis of different cancer types can be useful for several clinical applications. One example is to develop a biomarker panel for diagnostics of symptomatic patients as it has been successfully done in other diagnoses [12]. Increased basic knowledge of the mechanisms of glioma development could also help discover novel therapeutic targets, in analogy with how PARP inhibitors were discovered as a therapy in BRCA1 positive breast cancer patients [13]. For glioma, there is no robust blood test in diagnostics, even if some different pre-diagnostic biomarkers such as metabolites have been suggested [14]. Current therapeutic options have limited success and novel effective targeted treatments for glioma are urgently needed to improve survival.\nThe present study highlights a clear pattern of germline genetic variants associated with IDH-mutant and IDH-wildtype glioma, respectively (Figure 2). The variants with lowest frequency and strongest effect size are those most likely to be possible to incorporate in a clinical setting as it was shown in the recent study by Eckel-Passow et al. [10]. In the meta-analyses, we observe an association with all glioma for the TP53 gene variant and the TERT gene variant (Figure 1, group all, indicated in red). The TP53 variant is relatively rare, and its function is associated with both somatic loss of heterozygosity in the region and disrupted TP53 mRNA termination, as shown through previous studies of expression arrays in the TCGA dataset [15,16]. We did not find any differences in expression in the eQTL analyses (Table S3a). Furthermore, TP53 mutations are generally rare in glioma families [17,18]. TP53 is currently tested as a target for therapy, but as yet, no method has been introduced as a common treatment in any type of cancer [18].\nTERT encodes for telomerase reverse transcriptase, which has a function in telomere maintenance [19]. The TERT genetic risk variant has been associated with both glioma risk and telomere length indicating a functional effect through telomere regulation [20,21]. Longer leukocyte telomere length has been associated with increased risk of glioma [22,23]. The direct analyses of the single variant in TERT did not show any association with gene expression. However, recent transcriptome-wide association analysis (TWAS) using gene-based approaches that aggregate the effects of multiple variants suggests that the effect of TERT gene variants is mediated by transcription levels of the TERT gene [24]. The TWAS reported an association between genetically predicted TERT gene expression levels and risk of both GBM and non-GBM, which is in line with our finding that the TERT gene variant is associated with risk of glioma, regardless of IDH mutation status. One plausible mechanism of action for the TERT genetic variant is through methylation changes, considering that variants in the genomic area have been associated with lower methylation of a CpG site near the TERT transcription start site, cg23827991 [25,26]. Furthermore, the risk allele of rs10069690 has been shown to create an alternative splice donor site leading to a decrease in telomerase activity [26,27]. The genomic area is pleiotropic, and it is also possible that the variant exerts its function through a telomerase-independent pathway (alternative lengthening of telomeres) rather than by upregulating telomerase activity [28]. Several clinical trials that target TERT and telomere function are ongoing for different types of diseases but currently not for glioma [19]."}