Pub Date : 2019-05-01DOI: 10.18632/oncoscience.481
C. H. Marshall, E. Imada, Zhuojun Tang, L. Marchionni, E. Antonarakis
Inactivating CDK12 alterations have been reported in ovarian and prostate cancers and may have therapeutic implications; however, the prevalence of these mutations across other cancer types is unknown. We searched the cBioPortal and GENIE Project (public release v4.1) databases for cancer types with > 200 sequenced cases, that included patients with metastatic disease, and in which the occurrence of at least monoallelic CDK12 alterations was > 1%. The prevalence of at least monoallelic CDK12 mutations was highest in bladder cancer (3.7%); followed by prostate (3.4%), esophago-gastric (2.1%) and uterine cancers (2.1%). Biallelic CDK12 inactivation was highest in prostate cancer (1.8%), followed by ovarian (1.0%) and bladder cancers (0.5%). These results are the first (to our knowledge) to estimate the prevalence of monoallelic and biallelic CDK12 mutations across multiple cancer types encompassing over 15,000 cases.
{"title":"CDK12 inactivation across solid tumors: an actionable genetic subtype","authors":"C. H. Marshall, E. Imada, Zhuojun Tang, L. Marchionni, E. Antonarakis","doi":"10.18632/oncoscience.481","DOIUrl":"https://doi.org/10.18632/oncoscience.481","url":null,"abstract":"Inactivating CDK12 alterations have been reported in ovarian and prostate cancers and may have therapeutic implications; however, the prevalence of these mutations across other cancer types is unknown. We searched the cBioPortal and GENIE Project (public release v4.1) databases for cancer types with > 200 sequenced cases, that included patients with metastatic disease, and in which the occurrence of at least monoallelic CDK12 alterations was > 1%. The prevalence of at least monoallelic CDK12 mutations was highest in bladder cancer (3.7%); followed by prostate (3.4%), esophago-gastric (2.1%) and uterine cancers (2.1%). Biallelic CDK12 inactivation was highest in prostate cancer (1.8%), followed by ovarian (1.0%) and bladder cancers (0.5%). These results are the first (to our knowledge) to estimate the prevalence of monoallelic and biallelic CDK12 mutations across multiple cancer types encompassing over 15,000 cases.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"6 1","pages":"312 - 316"},"PeriodicalIF":0.0,"publicationDate":"2019-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73363342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-05-01DOI: 10.18632/oncoscience.483
A. Ray, B. Ray
Increased level of an inflammation-responsive transcription factor called serum amyloid A-activating factor (SAF-1) has been linked to the pathogenesis in human breast cancer. SAF-1 is found to promote vascular endothelial growth factor (VEGF) expression in breast carcinoma cells and boost angiogenesis. In an effort to develop a cellular mechanism to control VEGF expression, we sought to limit SAF-1 activity in breast cancer cells. We report here several targets within the SAF-1 mRNA for binding of microRNA-125b (miR-125b) and we show that VEGF expression is reduced in breast cancer cells when SAF-1 level is reduced with the microRNA action. Within the 3' un-translated region (UTR) of SAF-1 transcript, we have identified four highly conserved miR-125b responsive elements. We show that these miR-125b binding sites mediate repression of SAF-1 by miR-125b. Ectopic expression of miR-125b in nonmetastatic and metastatic breast cancer cells repressed SAF-1-mediated activity on VEGF promoter function and inhibited cancer cell migration and invasion potentials in vitro. Together, these results suggest that termination of SAF-1 function by miR-125b could be developed as a potential anti-VEGF and anti-angiogenic agent, which has high clinical relevance.
{"title":"Suppression of vascular endothelial growth factor expression in breast cancer cells by microRNA-125b-mediated attenuation of serum amyloid A activating factor-1 level","authors":"A. Ray, B. Ray","doi":"10.18632/oncoscience.483","DOIUrl":"https://doi.org/10.18632/oncoscience.483","url":null,"abstract":"Increased level of an inflammation-responsive transcription factor called serum amyloid A-activating factor (SAF-1) has been linked to the pathogenesis in human breast cancer. SAF-1 is found to promote vascular endothelial growth factor (VEGF) expression in breast carcinoma cells and boost angiogenesis. In an effort to develop a cellular mechanism to control VEGF expression, we sought to limit SAF-1 activity in breast cancer cells. We report here several targets within the SAF-1 mRNA for binding of microRNA-125b (miR-125b) and we show that VEGF expression is reduced in breast cancer cells when SAF-1 level is reduced with the microRNA action. Within the 3' un-translated region (UTR) of SAF-1 transcript, we have identified four highly conserved miR-125b responsive elements. We show that these miR-125b binding sites mediate repression of SAF-1 by miR-125b. Ectopic expression of miR-125b in nonmetastatic and metastatic breast cancer cells repressed SAF-1-mediated activity on VEGF promoter function and inhibited cancer cell migration and invasion potentials in vitro. Together, these results suggest that termination of SAF-1 function by miR-125b could be developed as a potential anti-VEGF and anti-angiogenic agent, which has high clinical relevance.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"399 1","pages":"337 - 348"},"PeriodicalIF":0.0,"publicationDate":"2019-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80057927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-12-21DOI: 10.18632/oncoscience.333
Stefanie B. Marquez-Vilendrer, S. Rai, Sarah J B Gramling, Li Lu, D. Reisman
The SWI/SNF complex is an important regulator of gene expression that functions by interacting with a diverse array of cellular proteins. The catalytic subunits of SWI/SNF, BRG1 and BRM, are frequently lost alone or concomitantly in a range of different cancer types. This loss abrogates SWI/SNF complex function as well as the functions of proteins that are required for SWI/SNF function, such as RB1 and TP53. Yet while both proteins are known to be dependent on SWI/SNF, we found that BRG1, but not BRM, is functionally linked to RB1, such that loss of BRG1 can directly or indirectly inactivate the RB1 pathway. This newly discovered dependence of RB1 on BRG1 is important because it explains why BRG1 loss can blunt the growth-inhibitory effect of tyrosine kinase inhibitors (TKIs). We also observed that selection for Trp53 mutations occurred in Brm-positive tumors but did not occur in Brm-negative tumors. Hence, these data indicate that, during cancer development, Trp53 is functionally dependent on Brm but not Brg1. Our findings show for the first time the key differences in Brm- and Brg1-specific SWI/SNF complexes and help explain why concomitant loss of Brg1 and Brm frequently occurs in cancer, as well as how their loss impacts cancer development.
{"title":"BRG1 and BRM loss selectively impacts RB and P53, respectively: BRG1 and BRM have differential functions in vivo","authors":"Stefanie B. Marquez-Vilendrer, S. Rai, Sarah J B Gramling, Li Lu, D. Reisman","doi":"10.18632/oncoscience.333","DOIUrl":"https://doi.org/10.18632/oncoscience.333","url":null,"abstract":"The SWI/SNF complex is an important regulator of gene expression that functions by interacting with a diverse array of cellular proteins. The catalytic subunits of SWI/SNF, BRG1 and BRM, are frequently lost alone or concomitantly in a range of different cancer types. This loss abrogates SWI/SNF complex function as well as the functions of proteins that are required for SWI/SNF function, such as RB1 and TP53. Yet while both proteins are known to be dependent on SWI/SNF, we found that BRG1, but not BRM, is functionally linked to RB1, such that loss of BRG1 can directly or indirectly inactivate the RB1 pathway. This newly discovered dependence of RB1 on BRG1 is important because it explains why BRG1 loss can blunt the growth-inhibitory effect of tyrosine kinase inhibitors (TKIs). We also observed that selection for Trp53 mutations occurred in Brm-positive tumors but did not occur in Brm-negative tumors. Hence, these data indicate that, during cancer development, Trp53 is functionally dependent on Brm but not Brg1. Our findings show for the first time the key differences in Brm- and Brg1-specific SWI/SNF complexes and help explain why concomitant loss of Brg1 and Brm frequently occurs in cancer, as well as how their loss impacts cancer development.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"39 1","pages":"337 - 350"},"PeriodicalIF":0.0,"publicationDate":"2016-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86602387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-12-21DOI: 10.18632/oncoscience.334
Rui Lu, G. Wang
One major goal of cancer research is to identify tumor-specific mechanisms that sustain cell proliferation or survival and to develop the corresponding therapies that target selectively against tumor. Recent sequencing of primary tumor samples supports that aberration of chromatin modification and epigenetic states plays a central role in oncogenesis. For example, mutation of DNA methyltransferase 3A (DNMT3A, Figure 1) occurs in approximately 20-30% of acute myeloid leukemia (AML) and 5-15% of other hematological malignancies and disorders, making DNMT3A one of the most frequently mutated genes in blood cancer [1]; genes encoding chromatin-remodeling protein complexes are found recurrently mutated or deleted in various tumors. Thus, DNMT3A and ATP-dependent chromatin remodelers appear to function as tumor suppressors, most likely, in a context-dependent manner. However, it remains elusive how alteration of chromatin-modifying machineries contributes to tumorigenesis, and mechanism-based therapeutic approaches are to be developed. Chromatin modifications ensure distinctive cellular identities. Past studies have shed light on several principles in chromatin modifications. One important property is reversibility. Epigenomic states are reset in response to developmental or environmental cues such as differentiation. Epigenetic changes are mediated by antagonizing enzymes that ‘write’ or ‘erase’ specific chromatin modification, exemplified by DNA methyltransferase or demethylase, and histone acetyltransferase (HAT) or deacetylase (HDAC). Second, epigenetic states can be relatively stable over cell divisions. Such ‘inheritance’ is partly owing to self-recruitment of modifying enzymes to promote self-propagation. Furthermore, different chromatin modifications that fall into the same gene-active or gene-repressive category often cooperate forming a selfreinforcement network. For example, methylated DNA is ‘read’ by MeCP2, which recruits HDACs to deacetylate histones (Figure 1). Due to the epigenetic crosstalk via antagonizing and reinforcing networks, one would Editorial
{"title":"Gene enhancer deregulation and epigenetic vulnerability","authors":"Rui Lu, G. Wang","doi":"10.18632/oncoscience.334","DOIUrl":"https://doi.org/10.18632/oncoscience.334","url":null,"abstract":"One major goal of cancer research is to identify tumor-specific mechanisms that sustain cell proliferation or survival and to develop the corresponding therapies that target selectively against tumor. Recent sequencing of primary tumor samples supports that aberration of chromatin modification and epigenetic states plays a central role in oncogenesis. For example, mutation of DNA methyltransferase 3A (DNMT3A, Figure 1) occurs in approximately 20-30% of acute myeloid leukemia (AML) and 5-15% of other hematological malignancies and disorders, making DNMT3A one of the most frequently mutated genes in blood cancer [1]; genes encoding chromatin-remodeling protein complexes are found recurrently mutated or deleted in various tumors. Thus, DNMT3A and ATP-dependent chromatin remodelers appear to function as tumor suppressors, most likely, in a context-dependent manner. However, it remains elusive how alteration of chromatin-modifying machineries contributes to tumorigenesis, and mechanism-based therapeutic approaches are to be developed. Chromatin modifications ensure distinctive cellular identities. Past studies have shed light on several principles in chromatin modifications. One important property is reversibility. Epigenomic states are reset in response to developmental or environmental cues such as differentiation. Epigenetic changes are mediated by antagonizing enzymes that ‘write’ or ‘erase’ specific chromatin modification, exemplified by DNA methyltransferase or demethylase, and histone acetyltransferase (HAT) or deacetylase (HDAC). Second, epigenetic states can be relatively stable over cell divisions. Such ‘inheritance’ is partly owing to self-recruitment of modifying enzymes to promote self-propagation. Furthermore, different chromatin modifications that fall into the same gene-active or gene-repressive category often cooperate forming a selfreinforcement network. For example, methylated DNA is ‘read’ by MeCP2, which recruits HDACs to deacetylate histones (Figure 1). Due to the epigenetic crosstalk via antagonizing and reinforcing networks, one would Editorial","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"11 1","pages":"299 - 301"},"PeriodicalIF":0.0,"publicationDate":"2016-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81830707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-12-16DOI: 10.18632/oncoscience.332
N. Djouder
Glucose is partly metabolized through the glucose sensing hexosamine biosynthetic pathway (HBP) leading to the formation of an end product called acetylated amino sugar nucleotide uridine 5'-diphospho-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAC serves as a donor substrate during O-GlcNAcylation (O-linked β-N-acetylglucosamine or O-GlcNAc) [1]. Serine or threonine residues of nuclear and cytoplasmic proteins are directly O-GlcNAcylated, competing with phosphorylation. O-GlcNAcylation is catalyzed by one unique enzyme called O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). O-GlcNAcylation is cleaved and removed by another one enzyme called N-acetyl-β-D-glucosaminidase (OGA) [1]. The existence of single and unique enzymes (OGT and OGA) acting on various different substrates suggest that enzyme activity can be modulated by binding partners in response to glucose levels [1]. O-GlcNAcylation levels are very dynamic and cycles rapidly, fluctuating in response to glucose concentrations influencing cell signaling pathways [1]. O-GlcNAcylation is thus relevant to various chronic human diseases such as diabetes, cardiovascular and neurodegenerative disorders and cancer. For example, OGT promotes aneuploidy, regulates cell-cycling via HCF-1 cleavage, and participates in regulatory links between metabolic changes and carcinogenesis [2]. Changes in OGA or OGT activity and hence, in O-GlcNAcylation levels may occur in human breast cancer and hepatocellular carcinoma (HCC) tissues [1]. The oncoprotein c-MYC is also O-GlcNAcylated. c-MYC protein is very unstable; its levels and activity are regulated by ubiquitination and proteasomal degradation, initiated by its phosphorylation at Thr-58 by GSK3β. Thr-58 is an OGT target which regulates c-MYC stability. O-GlcNAcylation at Thr-58 stabilizes c-MYC, promoting tumorigenesis [1]. Unconventional prefoldin RPB5 interactor (URI) binds and modulates OGT activity in response to glucose concentrations. In presence of glucose, URI, OGT and protein phosphatase 1 gamma (PP1γ) form a heterotrimeric complex. Glucose deprivation induces anaplerotic reactions, increasing ATP/cAMP levels, thereby activating PKA which in turn, phosphorylates URI at Ser-371. Phosphorylated URI frees PP1γ from the heterotrimeric complex and, URI becomes a potent inhibitor of OGT [1]. PKA reportedly forms a mitochondrial complex with PP1 catalytic units and the pro-apoptotic Bcl-2-associated death promoter (BAD) that influences glucose homeostasis [3]. Thus, URI/OGT/PP1γ complex may integrate glucose metabolism, possibly through a mitochondrial supra-molecular complex including PKA and BAD [3,4]. Abnormal glucose metabolism and BAD requirement in glucose deprivation-induced death is reported in Bad knockout and non-phosphorylatable BAD(3SA) knockin mice [3,5]. BAD is thus an apoptotic sentinel that monitors glucose signaling. Notably, OGT overexpression in a transgenic mouse model yields a type 2 diabetes (T2D) phenotype with insulin resist
葡萄糖通过葡萄糖感应己糖胺生物合成途径(HBP)部分代谢，导致最终产物乙酰化氨基糖核苷酸尿苷5'-二磷酸- n -乙酰氨基葡萄糖(UDP-GlcNAc)的形成。在o - glcn酰化(O-linked β- n -乙酰氨基葡萄糖或O-GlcNAc)过程中，UDP-GlcNAC作为供体底物[1]。核蛋白和细胞质蛋白的丝氨酸或苏氨酸残基直接被o - glcn酰化，与磷酸化相互竞争。O-GlcNAc酰化是由一种称为o -连接n -乙酰氨基葡萄糖(O-GlcNAc)转移酶(OGT)的独特酶催化的。o - glcn酰化被另一种称为n -乙酰-β- d -氨基葡萄糖酶(OGA)的酶切割和去除[1]。单一和独特的酶(OGT和OGA)作用于各种不同的底物，表明酶的活性可以通过结合伙伴来调节，以响应葡萄糖水平[1]。o - glcnac酰化水平是非常动态和快速循环的，随着葡萄糖浓度影响细胞信号通路而波动[1]。因此，o - glcn酰化与各种慢性人类疾病，如糖尿病、心血管和神经退行性疾病以及癌症有关。例如，OGT促进非整倍体，通过HCF-1切割调节细胞周期，并参与代谢变化与癌变之间的调节联系[2]。人类乳腺癌和肝细胞癌(HCC)组织中可能发生OGA或OGT活性以及o - glcn酰化水平的变化[1]。癌蛋白c-MYC也被o - glcn酰化。c-MYC蛋白非常不稳定;其水平和活性受泛素化和蛋白酶体降解调控，泛素化和蛋白酶体降解由GSK3β在Thr-58位点磷酸化引发。Thr-58是调节c-MYC稳定性的OGT靶点。Thr-58位点的o - glcn酰化稳定c-MYC，促进肿瘤发生[1]。非常规折叠蛋白RPB5相互作用因子(URI)结合并调节葡萄糖浓度对OGT活性的响应。在葡萄糖存在下，URI、OGT和蛋白磷酸酶1γ (PP1γ)形成异三聚体复合物。葡萄糖剥夺诱导回缩反应，增加ATP/cAMP水平，从而激活PKA，进而使URI Ser-371位点磷酸化。磷酸化的URI将PP1γ从异三聚体复合物中释放出来，URI成为一种有效的OGT抑制剂[1]。据报道，PKA与PP1催化单元和影响葡萄糖稳态的促凋亡bcl -2相关死亡启动子(BAD)形成线粒体复合物[3]。因此，URI/OGT/PP1γ复合物可能通过包括PKA和BAD在内的线粒体超分子复合物整合葡萄糖代谢[3,4]。据报道，在BAD敲除和非磷酸化BAD(3SA)敲除小鼠中，葡萄糖剥夺引起的死亡中存在异常的糖代谢和BAD需求[3,5]。因此BAD是一个凋亡哨兵，监视葡萄糖信号。值得注意的是，在转基因小鼠模型中，OGT过表达会产生伴有胰岛素抵抗和高瘦素血症的2型糖尿病(T2D)表型[6]。此外,……
{"title":"Adaptive survival mechanism to glucose restrictions","authors":"N. Djouder","doi":"10.18632/oncoscience.332","DOIUrl":"https://doi.org/10.18632/oncoscience.332","url":null,"abstract":"Glucose is partly metabolized through the glucose sensing hexosamine biosynthetic pathway (HBP) leading to the formation of an end product called acetylated amino sugar nucleotide uridine 5'-diphospho-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAC serves as a donor substrate during O-GlcNAcylation (O-linked β-N-acetylglucosamine or O-GlcNAc) [1]. Serine or threonine residues of nuclear and cytoplasmic proteins are directly O-GlcNAcylated, competing with phosphorylation. O-GlcNAcylation is catalyzed by one unique enzyme called O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). O-GlcNAcylation is cleaved and removed by another one enzyme called N-acetyl-β-D-glucosaminidase (OGA) [1]. The existence of single and unique enzymes (OGT and OGA) acting on various different substrates suggest that enzyme activity can be modulated by binding partners in response to glucose levels [1]. O-GlcNAcylation levels are very dynamic and cycles rapidly, fluctuating in response to glucose concentrations influencing cell signaling pathways [1]. O-GlcNAcylation is thus relevant to various chronic human diseases such as diabetes, cardiovascular and neurodegenerative disorders and cancer. For example, OGT promotes aneuploidy, regulates cell-cycling via HCF-1 cleavage, and participates in regulatory links between metabolic changes and carcinogenesis [2]. Changes in OGA or OGT activity and hence, in O-GlcNAcylation levels may occur in human breast cancer and hepatocellular carcinoma (HCC) tissues [1]. The oncoprotein c-MYC is also O-GlcNAcylated. c-MYC protein is very unstable; its levels and activity are regulated by ubiquitination and proteasomal degradation, initiated by its phosphorylation at Thr-58 by GSK3β. Thr-58 is an OGT target which regulates c-MYC stability. O-GlcNAcylation at Thr-58 stabilizes c-MYC, promoting tumorigenesis [1]. Unconventional prefoldin RPB5 interactor (URI) binds and modulates OGT activity in response to glucose concentrations. In presence of glucose, URI, OGT and protein phosphatase 1 gamma (PP1γ) form a heterotrimeric complex. Glucose deprivation induces anaplerotic reactions, increasing ATP/cAMP levels, thereby activating PKA which in turn, phosphorylates URI at Ser-371. Phosphorylated URI frees PP1γ from the heterotrimeric complex and, URI becomes a potent inhibitor of OGT [1]. PKA reportedly forms a mitochondrial complex with PP1 catalytic units and the pro-apoptotic Bcl-2-associated death promoter (BAD) that influences glucose homeostasis [3]. Thus, URI/OGT/PP1γ complex may integrate glucose metabolism, possibly through a mitochondrial supra-molecular complex including PKA and BAD [3,4]. Abnormal glucose metabolism and BAD requirement in glucose deprivation-induced death is reported in Bad knockout and non-phosphorylatable BAD(3SA) knockin mice [3,5]. BAD is thus an apoptotic sentinel that monitors glucose signaling. Notably, OGT overexpression in a transgenic mouse model yields a type 2 diabetes (T2D) phenotype with insulin resist","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"16 1","pages":"302 - 303"},"PeriodicalIF":0.0,"publicationDate":"2016-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84351843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-12-09DOI: 10.18632/oncoscience.331
M. V. van Maaren, P. Poortmans, S. Siesling
There is an ongoing debate regarding the use of randomised controlled trials (RCTs) versus observational studies when investigating treatment effects in clinical practice [1]. This holds especially true for the comparison of breast-conserving therapy (BCT) and mastectomy (MAST), which gained much attention since the publication of our observational study in Lancet Oncology [2]. RCTs are highly appreciated as they are close to generate perfectly unbiased treatment comparison estimates. Treatment groups in a RCT are expected to be exchangeable; even when switching the treatment between the compared groups, results will be similar and are solely the effect of the treatment under study. Clinical decisions are largely based on this type of evidence. But is this always the best evidence? Is it always feasible or ethical? In the current era of personalised medicine and 'big data', clinical interpretation of an abundance of data (clinical reasoning) is becoming more and more crucial. It integrates all available and relevant information that may contribute to the best clinical decision-making for individual patients. This generally starts with existing guidelines, completed by evidence extracted from observational studies and clinicians' experiences [3]. Importantly, the patient's preference plays an important role in (shared) decision-making. In general, it is difficult to translate the overall results of a RCT in the response of an individual patient to the investigated treatment. Even for patients with identical characteristics to those in the trial population, the overall treatment effect observed in RCTs would only apply if the probability of treatment benefit and detriment was equally distributed in every individual participant [3]. Often, evidence forming the basis of treatment guidelines are based on RCTs conducted a long time ago, while observational studies include a more recently diagnosed population. For BCT and MAST, the trials were all conducted in the eighties. Another important discrepancy between the RCT populations and the real-world population is the increasing share of elderly breast cancer patients in the latter. This is not only due to the ageing population, but also to early detection of breast cancer in the national screening program (which upper age limit is 75 years in the Netherlands), leading to a higher incidence in the elderly. Furthermore, diagnostic and surgical procedures as well as local and systemic therapies improved considerably. Moreover, increasing knowledge about the biological features of breast tumours led to the introduction of more advanced tumour-directed therapies. The combination of these improvements are very likely to …
{"title":"Breast-conserving therapy versus mastectomy","authors":"M. V. van Maaren, P. Poortmans, S. Siesling","doi":"10.18632/oncoscience.331","DOIUrl":"https://doi.org/10.18632/oncoscience.331","url":null,"abstract":"There is an ongoing debate regarding the use of randomised controlled trials (RCTs) versus observational studies when investigating treatment effects in clinical practice [1]. This holds especially true for the comparison of breast-conserving therapy (BCT) and mastectomy (MAST), which gained much attention since the publication of our observational study in Lancet Oncology [2]. RCTs are highly appreciated as they are close to generate perfectly unbiased treatment comparison estimates. Treatment groups in a RCT are expected to be exchangeable; even when switching the treatment between the compared groups, results will be similar and are solely the effect of the treatment under study. Clinical decisions are largely based on this type of evidence. But is this always the best evidence? Is it always feasible or ethical? In the current era of personalised medicine and 'big data', clinical interpretation of an abundance of data (clinical reasoning) is becoming more and more crucial. It integrates all available and relevant information that may contribute to the best clinical decision-making for individual patients. This generally starts with existing guidelines, completed by evidence extracted from observational studies and clinicians' experiences [3]. Importantly, the patient's preference plays an important role in (shared) decision-making. In general, it is difficult to translate the overall results of a RCT in the response of an individual patient to the investigated treatment. Even for patients with identical characteristics to those in the trial population, the overall treatment effect observed in RCTs would only apply if the probability of treatment benefit and detriment was equally distributed in every individual participant [3]. Often, evidence forming the basis of treatment guidelines are based on RCTs conducted a long time ago, while observational studies include a more recently diagnosed population. For BCT and MAST, the trials were all conducted in the eighties. Another important discrepancy between the RCT populations and the real-world population is the increasing share of elderly breast cancer patients in the latter. This is not only due to the ageing population, but also to early detection of breast cancer in the national screening program (which upper age limit is 75 years in the Netherlands), leading to a higher incidence in the elderly. Furthermore, diagnostic and surgical procedures as well as local and systemic therapies improved considerably. Moreover, increasing knowledge about the biological features of breast tumours led to the introduction of more advanced tumour-directed therapies. The combination of these improvements are very likely to …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"58 1","pages":"304 - 305"},"PeriodicalIF":0.0,"publicationDate":"2016-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80225806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-12-09DOI: 10.18632/oncoscience.330
Michaël Cerezo, R. Benhida, S. Rocchi
Melanoma is the most aggressive form of skin cancer. Recently, significant progress has emerged with the development of new strategies in melanoma treatment. We currently have specific BRAF and MAP3K/MEK inhibitors. However, after a short period of remission, melanomas acquire drug resistance and recurrence of metastases is observed in almost all cases [1]. Second, immunotherapies targeted against CTLA4 and PD1, developed to reactivate the antitumor immune response of the patient, result in an objective and long-lasting response in only approximately 30% of patients [2]. Nevertheless, more than 50% of patients are currently in treatment failure. Therefore, identification of new potential targets is an urgent need to improved melanoma treatment. One promising strategy is the targeting of the Unfolded Protein Response pathway which appears as an emerging pathway to selectively target cancer cells. Indeed, neoplasic growth requires synthesis of lot of different proteins and Unfolded Protein Response is activated to deal with the high flux of proteins processed through the Endoplasmic Reticulum to maintained homeostasis [3]. Recently, we have identified a new molecules family, Thiazole Benzensulfonamides (TZB), whose HA15 (1a) molecule appears as the lead compound, that induce an elevated and maintained Endoplasmic Reticulum stress specifically in cancer cells without any adverse events in normal cells [4] (Figure 1). Briefly, HA15 induces death of all melanoma cells independently of their mutational status and melanoma cells freshly isolated from patients both sensitive or resistant to BRAF inhibitors. HA15 exhibited also a strong efficacy in xenograft mouse models performed with melanoma cells sensitive and resistant to BRAF inhibitors without any sign of toxicity. We next performed pan-genomic, proteomic and biochemical studies to decipher the signaling pathway, the mechanism of action and the target of the best candidate. We identified BIP, an endoplasmic reticulum protein, as the specific target of our compound. We demonstrated clearly that the interaction between our compound and BIP increases Endoplasmic Reticulum Stress and leads to melanoma cell death by concomitant induction of autophagy and apoptosis mechanisms. Overexpression of target BIP in various cancers is described, it is thus not surprising that this molecule was also found to be active against other liquid and solid tumors. Taken together, our data suggest HA15 has an important impact on inhibition of melanoma growth by targeting ER stress, and may therefore be developed for treatment of melanoma and other cancers. Based on these strong data, we developed a lead optimization program in which two series of HA15 derivatives were synthesized that provided clear structure activity relationships. We then selected compound 1b as a new optimized analogue of HA15 [5]. This compound was found to be ten-fold more active then the parent compound on various cancer cell lines including melanom
{"title":"Targeting BIP to induce Endoplasmic Reticulum stress and cancer cell death","authors":"Michaël Cerezo, R. Benhida, S. Rocchi","doi":"10.18632/oncoscience.330","DOIUrl":"https://doi.org/10.18632/oncoscience.330","url":null,"abstract":"Melanoma is the most aggressive form of skin cancer. Recently, significant progress has emerged with the development of new strategies in melanoma treatment. We currently have specific BRAF and MAP3K/MEK inhibitors. However, after a short period of remission, melanomas acquire drug resistance and recurrence of metastases is observed in almost all cases [1]. Second, immunotherapies targeted against CTLA4 and PD1, developed to reactivate the antitumor immune response of the patient, result in an objective and long-lasting response in only approximately 30% of patients [2]. Nevertheless, more than 50% of patients are currently in treatment failure. Therefore, identification of new potential targets is an urgent need to improved melanoma treatment. One promising strategy is the targeting of the Unfolded Protein Response pathway which appears as an emerging pathway to selectively target cancer cells. Indeed, neoplasic growth requires synthesis of lot of different proteins and Unfolded Protein Response is activated to deal with the high flux of proteins processed through the Endoplasmic Reticulum to maintained homeostasis [3]. Recently, we have identified a new molecules family, Thiazole Benzensulfonamides (TZB), whose HA15 (1a) molecule appears as the lead compound, that induce an elevated and maintained Endoplasmic Reticulum stress specifically in cancer cells without any adverse events in normal cells [4] (Figure 1). Briefly, HA15 induces death of all melanoma cells independently of their mutational status and melanoma cells freshly isolated from patients both sensitive or resistant to BRAF inhibitors. HA15 exhibited also a strong efficacy in xenograft mouse models performed with melanoma cells sensitive and resistant to BRAF inhibitors without any sign of toxicity. We next performed pan-genomic, proteomic and biochemical studies to decipher the signaling pathway, the mechanism of action and the target of the best candidate. We identified BIP, an endoplasmic reticulum protein, as the specific target of our compound. We demonstrated clearly that the interaction between our compound and BIP increases Endoplasmic Reticulum Stress and leads to melanoma cell death by concomitant induction of autophagy and apoptosis mechanisms. Overexpression of target BIP in various cancers is described, it is thus not surprising that this molecule was also found to be active against other liquid and solid tumors. Taken together, our data suggest HA15 has an important impact on inhibition of melanoma growth by targeting ER stress, and may therefore be developed for treatment of melanoma and other cancers. Based on these strong data, we developed a lead optimization program in which two series of HA15 derivatives were synthesized that provided clear structure activity relationships. We then selected compound 1b as a new optimized analogue of HA15 [5]. This compound was found to be ten-fold more active then the parent compound on various cancer cell lines including melanom","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"69 6 1","pages":"306 - 307"},"PeriodicalIF":0.0,"publicationDate":"2016-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89125811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-11-23DOI: 10.18632/oncoscience.327
B. Carter, M. Andreeff
Bcr-Abl tyrosine kinase inhibitors (TKIs) have become the standard of care for patients with chronic myeloid leukemia (CML). Indeed, patients experience high response rates and long-term survival with continuous TKI treatment. However, TKIs rarely cure CML due to their inability to target CML stem cells. Consequently, CML will soon become the most prevalent leukemia with 100,000 patients in the U.S. alone. Long-term treatment with TKIs is extremely expensive, associated with side effects, and development of resistance in some patients. Resistance can fuel the progression to blast crisis (BC), which is associated with almost complete chemo-resistance and extremely poor treatment outcome. During the last decade, significant insights into CML stem cell biology and mechanisms of TKI resistance were gained leading to the development of combinatorial strategies to target CML stem/progenitor cells and to overcome TKI resistance [1,2]. We and others have established Bcl-2 family proteins as key apoptosis regulators and specifically anti-apoptotic Bcl-2 proteins as crucial survival factors for myeloid leukemia cells and stem/progenitor cells. Inhibition of anti-apoptotic Bcl-2 proteins with dual Bcl-2/Bcl-xL or pan-Bcl-2 inhibitors was shown to target CML stem/progenitor cells and enhance the therapeutic efficacy of TKIs [3,4]. The tumor suppressor p53 regulates apoptosis primarily by transcriptional activation of pro-apoptotic Bcl-2 family proteins. Although frequently mutated in solid tumors, p53 mutations are rare in CML. We demonstrated that the activation of p53 via inhibition of its negative regulator, MDM2, in combination with TKIs synergistically targeted quiescent CD34 + BC CML cells [5], and Holyoake recently reported that dual targeting of p53 and c-MYC selectively eliminated CML stem cells [6]. To improve specificity and efficacy, and minimize toxicity, it is important to recognize which Bcl-2 proteins are indispensable for CML stem cell survival. Until recently, most Bcl-2 inhibitors were relatively non-specific and targeted several Bcl-2 proteins. Furthermore, our knowledge of the expression of Bcl-2 family members in hematopoietic and CML stem/progenitor cells is essentially limited to RNA, not protein levels, primarily because stem/progenitor cells account for only a very small portion of total bone marrow (BM) cells. CyTOF (" cytometry by time-of-flight ") combines mass spectrometry and flow cytometry and constitutes a novel single cell proteomics system that can determine the expression of currently over 40 (potentially 120) cell surface and intracellular proteins simultaneously without the spectral overlap, and therefore able to determine the expression of multiple proteins/phosphoproteins in a phenotypically well-defined cell population. Using CyTOF, and an inducible …
Bcr-Abl酪氨酸激酶抑制剂(TKIs)已成为慢性髓性白血病(CML)患者的标准治疗。事实上，患者在持续TKI治疗中获得了高有效率和长期生存率。然而，由于TKIs不能靶向CML干细胞，因此很少能治愈CML。因此，CML将很快成为最普遍的白血病，仅在美国就有10万名患者。长期使用tki治疗非常昂贵，并且伴有副作用，一些患者还会产生耐药性。耐药可加速发展为blast危象(BC)，这与几乎完全的化疗耐药和极差的治疗结果有关。在过去的十年中，对CML干细胞生物学和TKI耐药机制的深入研究导致了针对CML干细胞/祖细胞的组合策略的发展，并克服了TKI耐药[1,2]。我们和其他人已经确定Bcl-2家族蛋白是关键的凋亡调节因子，特别是抗凋亡Bcl-2蛋白是髓系白血病细胞和干细胞/祖细胞的关键存活因子。双Bcl-2/Bcl-xL或泛Bcl-2抑制剂抑制抗凋亡Bcl-2蛋白可靶向CML干细胞/祖细胞并增强TKIs的治疗效果[3,4]。肿瘤抑制因子p53主要通过促凋亡Bcl-2家族蛋白的转录激活来调节细胞凋亡。尽管p53在实体瘤中经常发生突变，但在CML中很少发生突变。我们证明了p53通过抑制其负调节因子MDM2激活，与TKIs联合靶向静止CD34 + BC CML细胞[5]，Holyoake最近报道了p53和c-MYC的双重靶向选择性地消除CML干细胞[6]。为了提高特异性和疗效，减少毒性，认识哪些Bcl-2蛋白对CML干细胞存活是必不可少的是很重要的。直到最近，大多数Bcl-2抑制剂都是非特异性的，并且针对几种Bcl-2蛋白。此外，我们对Bcl-2家族成员在造血和CML干细胞/祖细胞中的表达的了解基本上局限于RNA水平，而不是蛋白质水平，主要是因为干细胞/祖细胞只占骨髓细胞总数的很小一部分。CyTOF(“飞行时间细胞术”)结合了质谱法和流式细胞术，构成了一种新的单细胞蛋白质组学系统，可以同时测定目前超过40种(可能120种)细胞表面和细胞内蛋白质的表达，而不存在光谱重叠，因此能够测定表型明确的细胞群中多种蛋白质/磷酸化蛋白的表达。利用细胞of和诱导…
{"title":"Eradication of CML stem cells","authors":"B. Carter, M. Andreeff","doi":"10.18632/oncoscience.327","DOIUrl":"https://doi.org/10.18632/oncoscience.327","url":null,"abstract":"Bcr-Abl tyrosine kinase inhibitors (TKIs) have become the standard of care for patients with chronic myeloid leukemia (CML). Indeed, patients experience high response rates and long-term survival with continuous TKI treatment. However, TKIs rarely cure CML due to their inability to target CML stem cells. Consequently, CML will soon become the most prevalent leukemia with 100,000 patients in the U.S. alone. Long-term treatment with TKIs is extremely expensive, associated with side effects, and development of resistance in some patients. Resistance can fuel the progression to blast crisis (BC), which is associated with almost complete chemo-resistance and extremely poor treatment outcome. During the last decade, significant insights into CML stem cell biology and mechanisms of TKI resistance were gained leading to the development of combinatorial strategies to target CML stem/progenitor cells and to overcome TKI resistance [1,2]. We and others have established Bcl-2 family proteins as key apoptosis regulators and specifically anti-apoptotic Bcl-2 proteins as crucial survival factors for myeloid leukemia cells and stem/progenitor cells. Inhibition of anti-apoptotic Bcl-2 proteins with dual Bcl-2/Bcl-xL or pan-Bcl-2 inhibitors was shown to target CML stem/progenitor cells and enhance the therapeutic efficacy of TKIs [3,4]. The tumor suppressor p53 regulates apoptosis primarily by transcriptional activation of pro-apoptotic Bcl-2 family proteins. Although frequently mutated in solid tumors, p53 mutations are rare in CML. We demonstrated that the activation of p53 via inhibition of its negative regulator, MDM2, in combination with TKIs synergistically targeted quiescent CD34 + BC CML cells [5], and Holyoake recently reported that dual targeting of p53 and c-MYC selectively eliminated CML stem cells [6]. To improve specificity and efficacy, and minimize toxicity, it is important to recognize which Bcl-2 proteins are indispensable for CML stem cell survival. Until recently, most Bcl-2 inhibitors were relatively non-specific and targeted several Bcl-2 proteins. Furthermore, our knowledge of the expression of Bcl-2 family members in hematopoietic and CML stem/progenitor cells is essentially limited to RNA, not protein levels, primarily because stem/progenitor cells account for only a very small portion of total bone marrow (BM) cells. CyTOF (\" cytometry by time-of-flight \") combines mass spectrometry and flow cytometry and constitutes a novel single cell proteomics system that can determine the expression of currently over 40 (potentially 120) cell surface and intracellular proteins simultaneously without the spectral overlap, and therefore able to determine the expression of multiple proteins/phosphoproteins in a phenotypically well-defined cell population. Using CyTOF, and an inducible …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"97 1","pages":"313 - 315"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79208122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-11-23DOI: 10.18632/oncoscience.326
H. Bid, S. Kerk
Angiogenesis is one of the most critical multi-step biological essentials affecting the development and progression of cancer. It has been explored for decades as a potential target for therapy after endless preclinical and clinical studies. Currently, conceptually promising FDA-approved agents, such as bevacizumab (Avastin, Genentech/Roche), sorafenib (Nexavar, Bayer), and sunitinib (Sutent, Pfizer), have twisted only modest effects in the clinic and do not result in lasting responses of cancer treatment [1]. Tumors have proven to be either intrinsic resistant or acquired resistance through evasion via mutation or recruitment of surplus pro-angiogenic factors [1]. Molecular targeted therapies comprising anti-antiangiogenic potential are becoming more widely accepted in drug discovery era as compared to established anticancer treatment approaches and have more promising results in numerous types of cancers. JQ1, a bromodomain inhibitor produced by James Bradner, (Tensha Therapeutics acquired by Roche) has direct antitumor and antiangiogenic properties. This small molecule inhibitor targets BRD4, a member of the bromodomain and extra-terminal (BET) family of transcription factors. BRD4 binds to acetylated lysine residues within chromatin, and recruits positive transcription elongation factor (P-TEFb) and other super enhancers involved in transcription. JQ-1 prevents the BRD4-acetylated lysine interaction by competitively binding to BRD4 and inhibiting transcription. In multiple myeloma (MM), a disease frequently associated with dysregulated BET activity, a direct interaction between BRD4 and IgH enhancers located within the MYC locus was observed. JQ1 prohibited this interaction, suppressed MYC transcription, and reduced the levels of downstream effectors. JQ1 treatment induced cell senescence and apoptosis in multiple MM cell lines, and slowed tumor growth and in orthotopic MM mouse models leading to increased survival [2]. The ability of JQ-1 to inhibit MYC transcription has important implications in angiogenesis via blocking VEGF, notch pathway, etc (Figure 1). One study observed that c-Myc knockout mice displayed dysfunctional endothelial cell activity and impaired vascular development in embryonic yolk sacs. Furthermore, the loss of c-Myc reduced the tumorogenicity and differentiation ability of embryonic stem (ES) cells. Reintroducing VEGF reversed the effects of c-Myc knockout. C-Myc also increased the expression of other pro-angiogenic factors such as angiopoietin-2 (ANG-2) and down-regulated anti-angiogenic factors like ANG-1 and thrombospondin-1 (TSP-1) [3]. Indeed, in a study with a transgenic mouse model of Myc oncogenesis, overexpressing Myc in pancreatic β cells quickly increased the expression of the inflammatory cytokine IL-1β, activating matrix metalloproteases (MMP) that in turn released VEGF-A sequestered in the extracellular matrix (ECM). VEGF-A localized to its …
{"title":"BET bromodomain inhibitor (JQ1) and tumor angiogenesis","authors":"H. Bid, S. Kerk","doi":"10.18632/oncoscience.326","DOIUrl":"https://doi.org/10.18632/oncoscience.326","url":null,"abstract":"Angiogenesis is one of the most critical multi-step biological essentials affecting the development and progression of cancer. It has been explored for decades as a potential target for therapy after endless preclinical and clinical studies. Currently, conceptually promising FDA-approved agents, such as bevacizumab (Avastin, Genentech/Roche), sorafenib (Nexavar, Bayer), and sunitinib (Sutent, Pfizer), have twisted only modest effects in the clinic and do not result in lasting responses of cancer treatment [1]. Tumors have proven to be either intrinsic resistant or acquired resistance through evasion via mutation or recruitment of surplus pro-angiogenic factors [1]. Molecular targeted therapies comprising anti-antiangiogenic potential are becoming more widely accepted in drug discovery era as compared to established anticancer treatment approaches and have more promising results in numerous types of cancers. JQ1, a bromodomain inhibitor produced by James Bradner, (Tensha Therapeutics acquired by Roche) has direct antitumor and antiangiogenic properties. This small molecule inhibitor targets BRD4, a member of the bromodomain and extra-terminal (BET) family of transcription factors. BRD4 binds to acetylated lysine residues within chromatin, and recruits positive transcription elongation factor (P-TEFb) and other super enhancers involved in transcription. JQ-1 prevents the BRD4-acetylated lysine interaction by competitively binding to BRD4 and inhibiting transcription. In multiple myeloma (MM), a disease frequently associated with dysregulated BET activity, a direct interaction between BRD4 and IgH enhancers located within the MYC locus was observed. JQ1 prohibited this interaction, suppressed MYC transcription, and reduced the levels of downstream effectors. JQ1 treatment induced cell senescence and apoptosis in multiple MM cell lines, and slowed tumor growth and in orthotopic MM mouse models leading to increased survival [2]. The ability of JQ-1 to inhibit MYC transcription has important implications in angiogenesis via blocking VEGF, notch pathway, etc (Figure 1). One study observed that c-Myc knockout mice displayed dysfunctional endothelial cell activity and impaired vascular development in embryonic yolk sacs. Furthermore, the loss of c-Myc reduced the tumorogenicity and differentiation ability of embryonic stem (ES) cells. Reintroducing VEGF reversed the effects of c-Myc knockout. C-Myc also increased the expression of other pro-angiogenic factors such as angiopoietin-2 (ANG-2) and down-regulated anti-angiogenic factors like ANG-1 and thrombospondin-1 (TSP-1) [3]. Indeed, in a study with a transgenic mouse model of Myc oncogenesis, overexpressing Myc in pancreatic β cells quickly increased the expression of the inflammatory cytokine IL-1β, activating matrix metalloproteases (MMP) that in turn released VEGF-A sequestered in the extracellular matrix (ECM). VEGF-A localized to its …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"3 1","pages":"316 - 317"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87776969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-11-23DOI: 10.18632/oncoscience.325
R. C. Poulos, J. W. Wong
In recent years, somatic mutations in cis-regulatory elements of cancer genomes have become a focus of much research. A landmark discovery occurred in 2013, in which recurrent somatic mutations were identified in the promoter of the key cancer-associated gene, TERT (reviewed in [1]). In the search for other highly recurrent cis-regulatory mutations which may serve as novel driver events, two papers, published in 2014 [2, 3], revealed somewhat surprising results. These studies investigated large cohorts of cancer genomes and found that, despite identifying many recurrent promoter mutations, few could be associated with gene expression changes. Of those that did alter gene expression, many of their target genes did not have strong links to cancer development. We also published similar unexpected findings in a genomewide survey of promoter mutations in the melanoma cellline, COLO829 [4]. The study showed that while some regulatory mutations can alter promoter activity (~17% of mutant promoter regions surveyed), one such mutation that was recurrent (~4.4%) in other melanomas was not associated with altered gene expression in actual cancer samples [4]. Remarkably, we additionally observed that of the 14 remaining promoter mutations surveyed to not alter promoter activity, five mutations were also recurrent in melanoma samples. Together these articles raised the question of why there are such high rates of recurrence among promoter mutations if many do not appear to arise due to their oncogenic ability to alter gene expression.
{"title":"Mutation hotspots in cis-regulatory regions in cancer","authors":"R. C. Poulos, J. W. Wong","doi":"10.18632/oncoscience.325","DOIUrl":"https://doi.org/10.18632/oncoscience.325","url":null,"abstract":"In recent years, somatic mutations in cis-regulatory elements of cancer genomes have become a focus of much research. A landmark discovery occurred in 2013, in which recurrent somatic mutations were identified in the promoter of the key cancer-associated gene, TERT (reviewed in [1]). In the search for other highly recurrent cis-regulatory mutations which may serve as novel driver events, two papers, published in 2014 [2, 3], revealed somewhat surprising results. These studies investigated large cohorts of cancer genomes and found that, despite identifying many recurrent promoter mutations, few could be associated with gene expression changes. Of those that did alter gene expression, many of their target genes did not have strong links to cancer development. We also published similar unexpected findings in a genomewide survey of promoter mutations in the melanoma cellline, COLO829 [4]. The study showed that while some regulatory mutations can alter promoter activity (~17% of mutant promoter regions surveyed), one such mutation that was recurrent (~4.4%) in other melanomas was not associated with altered gene expression in actual cancer samples [4]. Remarkably, we additionally observed that of the 14 remaining promoter mutations surveyed to not alter promoter activity, five mutations were also recurrent in melanoma samples. Together these articles raised the question of why there are such high rates of recurrence among promoter mutations if many do not appear to arise due to their oncogenic ability to alter gene expression.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"4 1","pages":"318 - 319"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83056216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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