Pub Date : 2023-08-09DOI: 10.1038/s41568-023-00613-2
Gabrielle Brewer
In this study, Conn et al. functionally link circular RNA and DNA interactions with chromosomal translocation in leukaemogenesis.
在这项研究中，Conn 等人从功能上将环状 RNA 和 DNA 的相互作用与白血病发生过程中的染色体易位联系起来。
{"title":"The circ du RNA","authors":"Gabrielle Brewer","doi":"10.1038/s41568-023-00613-2","DOIUrl":"10.1038/s41568-023-00613-2","url":null,"abstract":"In this study, Conn et al. functionally link circular RNA and DNA interactions with chromosomal translocation in leukaemogenesis.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 9","pages":"578-578"},"PeriodicalIF":78.5,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10068722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-03DOI: 10.1038/s41568-023-00603-4
Theophilus T. Tettey, Lorenzo Rinaldi, Gordon L. Hager
The human genome is organized into multiple structural layers, ranging from chromosome territories to progressively smaller substructures, such as topologically associating domains (TADs) and chromatin loops. These substructures, collectively referred to as long-range chromatin interactions (LRIs), have a significant role in regulating gene expression. TADs are regions of the genome that harbour groups of genes and regulatory elements that frequently interact with each other and are insulated from other regions, thereby preventing widespread uncontrolled DNA contacts. Chromatin loops formed within TADs through enhancer and promoter interactions are elastic, allowing transcriptional heterogeneity and stochasticity. Over the past decade, it has become evident that the 3D genome structure, also referred to as the chromatin architecture, is central to many transcriptional cellular decisions. In this Review, we delve into the intricate relationship between steroid receptors and LRIs, discussing how steroid receptors interact with and modulate these chromatin interactions. Genetic alterations in the many processes involved in organizing the nuclear architecture are often associated with the development of hormone-dependent cancers. A better understanding of the interplay between architectural proteins and hormone regulatory networks can ultimately be exploited to develop improved approaches for cancer treatment. This Review discusses the impact of steroid-receptor-mediated modifications of long-range chromatin interactions on transcriptional heterogeneity and the initiation, progression and therapy response of hormone-dependent cancers.
{"title":"Long-range gene regulation in hormone-dependent cancer","authors":"Theophilus T. Tettey, Lorenzo Rinaldi, Gordon L. Hager","doi":"10.1038/s41568-023-00603-4","DOIUrl":"10.1038/s41568-023-00603-4","url":null,"abstract":"The human genome is organized into multiple structural layers, ranging from chromosome territories to progressively smaller substructures, such as topologically associating domains (TADs) and chromatin loops. These substructures, collectively referred to as long-range chromatin interactions (LRIs), have a significant role in regulating gene expression. TADs are regions of the genome that harbour groups of genes and regulatory elements that frequently interact with each other and are insulated from other regions, thereby preventing widespread uncontrolled DNA contacts. Chromatin loops formed within TADs through enhancer and promoter interactions are elastic, allowing transcriptional heterogeneity and stochasticity. Over the past decade, it has become evident that the 3D genome structure, also referred to as the chromatin architecture, is central to many transcriptional cellular decisions. In this Review, we delve into the intricate relationship between steroid receptors and LRIs, discussing how steroid receptors interact with and modulate these chromatin interactions. Genetic alterations in the many processes involved in organizing the nuclear architecture are often associated with the development of hormone-dependent cancers. A better understanding of the interplay between architectural proteins and hormone regulatory networks can ultimately be exploited to develop improved approaches for cancer treatment. This Review discusses the impact of steroid-receptor-mediated modifications of long-range chromatin interactions on transcriptional heterogeneity and the initiation, progression and therapy response of hormone-dependent cancers.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 10","pages":"657-672"},"PeriodicalIF":78.5,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10308857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-31DOI: 10.1038/s41568-023-00608-z
Anna Dart
Girish et al. designed a method to genetically remove extra chromosomes from human aneuploid cancer cells to show that they are important for malignant growth and not just a bystander.
{"title":"Addicted to extra chromosomes","authors":"Anna Dart","doi":"10.1038/s41568-023-00608-z","DOIUrl":"10.1038/s41568-023-00608-z","url":null,"abstract":"Girish et al. designed a method to genetically remove extra chromosomes from human aneuploid cancer cells to show that they are important for malignant growth and not just a bystander.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 9","pages":"579-579"},"PeriodicalIF":78.5,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10472850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-27DOI: 10.1038/s41568-023-00604-3
Marie Will, Jackson Liang, Ciara Metcalfe, Sarat Chandarlapaty
The hormone receptor oestrogen receptor-α (ER) orchestrates physiological mammary gland development, breast carcinogenesis and the progression of breast tumours into lethal, treatment-refractory systemic disease. Selective antagonism of ER signalling has been one of the most successful therapeutic approaches in oncology, benefiting patients as both a cancer preventative measure and a cancer treatment strategy. However, resistance to anti-oestrogen therapy is a major clinical challenge. Over the past decade, we have gained an understanding of how breast cancers evolve under the pressure of anti-oestrogen therapy. This is best depicted by the case of oestrogen-independent mutations in the gene encoding ER (ESR1), which are virtually absent in primary breast cancer but highly prevalent (20–40%) in anti-oestrogen-treated metastatic disease. These and other findings highlight the ‘evolvability’ of ER+ breast cancer and the need to understand molecular processes by which this evolution occurs. Recent development and approval of next-generation ER antagonists to target ESR1-mutant breast cancer underscores the clinical importance of this evolvability and sets a new paradigm for the treatment of ER+ breast cancers. Although selective antagonism of oestrogen receptor signalling in breast cancer has been one of the most successful therapeutic approaches in oncology, resistance is a major clinical challenge. In this Review, Will et al. explore mechanisms of oestrogen-receptor-α-targeted therapeutic resistance and strategies to overcome it.
{"title":"Therapeutic resistance to anti-oestrogen therapy in breast cancer","authors":"Marie Will, Jackson Liang, Ciara Metcalfe, Sarat Chandarlapaty","doi":"10.1038/s41568-023-00604-3","DOIUrl":"10.1038/s41568-023-00604-3","url":null,"abstract":"The hormone receptor oestrogen receptor-α (ER) orchestrates physiological mammary gland development, breast carcinogenesis and the progression of breast tumours into lethal, treatment-refractory systemic disease. Selective antagonism of ER signalling has been one of the most successful therapeutic approaches in oncology, benefiting patients as both a cancer preventative measure and a cancer treatment strategy. However, resistance to anti-oestrogen therapy is a major clinical challenge. Over the past decade, we have gained an understanding of how breast cancers evolve under the pressure of anti-oestrogen therapy. This is best depicted by the case of oestrogen-independent mutations in the gene encoding ER (ESR1), which are virtually absent in primary breast cancer but highly prevalent (20–40%) in anti-oestrogen-treated metastatic disease. These and other findings highlight the ‘evolvability’ of ER+ breast cancer and the need to understand molecular processes by which this evolution occurs. Recent development and approval of next-generation ER antagonists to target ESR1-mutant breast cancer underscores the clinical importance of this evolvability and sets a new paradigm for the treatment of ER+ breast cancers. Although selective antagonism of oestrogen receptor signalling in breast cancer has been one of the most successful therapeutic approaches in oncology, resistance is a major clinical challenge. In this Review, Will et al. explore mechanisms of oestrogen-receptor-α-targeted therapeutic resistance and strategies to overcome it.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 10","pages":"673-685"},"PeriodicalIF":78.5,"publicationDate":"2023-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10099336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-25DOI: 10.1038/s41568-023-00607-0
Gabrielle Brewer
Inducing ferroptosis in cancer cells has become a realistic method for promoting cancer cell death. In this study, Nakarmua et al. identify a novel ferroptosis suppressor 1 (FSP1) inhibitor that promotes FSP1 relocalization through phase separation, priming ferroptosis and ultimately impairing tumour growth.
{"title":"FSP1 in cancer: not just a phase","authors":"Gabrielle Brewer","doi":"10.1038/s41568-023-00607-0","DOIUrl":"10.1038/s41568-023-00607-0","url":null,"abstract":"Inducing ferroptosis in cancer cells has become a realistic method for promoting cancer cell death. In this study, Nakarmua et al. identify a novel ferroptosis suppressor 1 (FSP1) inhibitor that promotes FSP1 relocalization through phase separation, priming ferroptosis and ultimately impairing tumour growth.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 9","pages":"578-578"},"PeriodicalIF":78.5,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10055205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-24DOI: 10.1038/s41568-023-00602-5
Amir Jassim, Eric P. Rahrmann, Ben D. Simons, Richard J. Gilbertson
Cancer has been a leading cause of death for decades. This dismal statistic has increased efforts to prevent the disease or to detect it early, when treatment is less invasive, relatively inexpensive and more likely to cure. But precisely how tissues are transformed continues to provoke controversy and debate, hindering cancer prevention and early intervention strategies. Various theories of cancer origins have emerged, including the suggestion that it is ‘bad luck’: the inevitable consequence of random mutations in proliferating stem cells. In this Review, we discuss the principal theories of cancer origins and the relative importance of the factors that underpin them. The body of available evidence suggests that developing and ageing tissues ‘walk a tightrope’, retaining adequate levels of cell plasticity to generate and maintain tissues while avoiding overstepping into transformation. Rather than viewing cancer as ‘bad luck’, understanding the complex choreography of cell intrinsic and extrinsic factors that characterize transformation holds promise to discover effective new ways to prevent, detect and stop cancer before it becomes incurable. Understanding how cell intrinsic and extrinsic factors combine to initiate transformation holds promise for the development of strategies to prevent, detect and treat cancer early. In this Review, Jassim et al. outline the various theories that have currently been proposed for cancer origins, and the determinants of cancer risk upon which they are based.
{"title":"Cancers make their own luck: theories of cancer origins","authors":"Amir Jassim, Eric P. Rahrmann, Ben D. Simons, Richard J. Gilbertson","doi":"10.1038/s41568-023-00602-5","DOIUrl":"10.1038/s41568-023-00602-5","url":null,"abstract":"Cancer has been a leading cause of death for decades. This dismal statistic has increased efforts to prevent the disease or to detect it early, when treatment is less invasive, relatively inexpensive and more likely to cure. But precisely how tissues are transformed continues to provoke controversy and debate, hindering cancer prevention and early intervention strategies. Various theories of cancer origins have emerged, including the suggestion that it is ‘bad luck’: the inevitable consequence of random mutations in proliferating stem cells. In this Review, we discuss the principal theories of cancer origins and the relative importance of the factors that underpin them. The body of available evidence suggests that developing and ageing tissues ‘walk a tightrope’, retaining adequate levels of cell plasticity to generate and maintain tissues while avoiding overstepping into transformation. Rather than viewing cancer as ‘bad luck’, understanding the complex choreography of cell intrinsic and extrinsic factors that characterize transformation holds promise to discover effective new ways to prevent, detect and stop cancer before it becomes incurable. Understanding how cell intrinsic and extrinsic factors combine to initiate transformation holds promise for the development of strategies to prevent, detect and treat cancer early. In this Review, Jassim et al. outline the various theories that have currently been proposed for cancer origins, and the determinants of cancer risk upon which they are based.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 10","pages":"710-724"},"PeriodicalIF":78.5,"publicationDate":"2023-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9919551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-21DOI: 10.1038/s41568-023-00599-x
Xin Yang, Siddhartha Kar, Antonis C. Antoniou, Paul D. P. Pharoah
Since the publication of the first genome-wide association study for cancer in 2007, thousands of common alleles that are associated with the risk of cancer have been identified. The relative risk associated with individual variants is small and of limited clinical significance. However, the combined effect of multiple risk variants as captured by polygenic scores (PGSs) may be much greater and therefore provide risk discrimination that is clinically useful. We review the considerable research efforts over the past 15 years for developing statistical methods for PGSs and their application in large-scale genome-wide association studies to develop PGSs for various cancers. We review the predictive performance of these PGSs and the multiple challenges currently limiting the clinical application of PGSs. Despite this, PGSs are beginning to be incorporated into clinical multifactorial risk prediction models to stratify risk in both clinical trials and clinical implementation studies. Since the advent of genome-wide association studies, thousands of common alleles have been linked with the risk of cancer. Here, Yang et al. review the development, utility and predictive power of polygenic risk scores and the ongoing debate about their potential for clinical application in cancer.
{"title":"Polygenic scores in cancer","authors":"Xin Yang, Siddhartha Kar, Antonis C. Antoniou, Paul D. P. Pharoah","doi":"10.1038/s41568-023-00599-x","DOIUrl":"10.1038/s41568-023-00599-x","url":null,"abstract":"Since the publication of the first genome-wide association study for cancer in 2007, thousands of common alleles that are associated with the risk of cancer have been identified. The relative risk associated with individual variants is small and of limited clinical significance. However, the combined effect of multiple risk variants as captured by polygenic scores (PGSs) may be much greater and therefore provide risk discrimination that is clinically useful. We review the considerable research efforts over the past 15 years for developing statistical methods for PGSs and their application in large-scale genome-wide association studies to develop PGSs for various cancers. We review the predictive performance of these PGSs and the multiple challenges currently limiting the clinical application of PGSs. Despite this, PGSs are beginning to be incorporated into clinical multifactorial risk prediction models to stratify risk in both clinical trials and clinical implementation studies. Since the advent of genome-wide association studies, thousands of common alleles have been linked with the risk of cancer. Here, Yang et al. review the development, utility and predictive power of polygenic risk scores and the ongoing debate about their potential for clinical application in cancer.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 9","pages":"619-630"},"PeriodicalIF":78.5,"publicationDate":"2023-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10440868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lessons in gastric adenocarcinoma from TCGA","authors":"Tiago Cordeiro Felismino, Felipe José Fernández Coimbra","doi":"10.1038/s41568-023-00606-1","DOIUrl":"10.1038/s41568-023-00606-1","url":null,"abstract":"In this Journal Club, Felismino and Coimbra discuss the impact of TCGA’s comprehensive molecular characterization of gastric adenocarcinoma.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 10","pages":"655-655"},"PeriodicalIF":78.5,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9836360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-12DOI: 10.1038/s41568-023-00598-y
James A. Fagin, Gnana P. Krishnamoorthy, Iñigo Landa
The genomic simplicity of differentiated cancers derived from thyroid follicular cells offers unique insights into how oncogenic drivers impact tumour phenotype. Essentially, the main oncoproteins in thyroid cancer activate nodes in the receptor tyrosine kinase–RAS–BRAF pathway, which constitutively induces MAPK signalling to varying degrees consistent with their specific biochemical mechanisms of action. The magnitude of the flux through the MAPK signalling pathway determines key elements of thyroid cancer biology, including differentiation state, invasive properties and the cellular composition of the tumour microenvironment. Progression of disease results from genomic lesions that drive immortalization, disrupt chromatin accessibility and cause cell cycle checkpoint dysfunction, in conjunction with a tumour microenvironment characterized by progressive immunosuppression. This Review charts the genomic trajectories of these common endocrine tumours, while connecting them to the biological states that they confer. In this Review, Fagin et al. outline the oncogenic drivers of the common endocrine tumours, which derive from thyroid follicular cells, and how these impact tumour phenotypes and disease progression.
{"title":"Pathogenesis of cancers derived from thyroid follicular cells","authors":"James A. Fagin, Gnana P. Krishnamoorthy, Iñigo Landa","doi":"10.1038/s41568-023-00598-y","DOIUrl":"10.1038/s41568-023-00598-y","url":null,"abstract":"The genomic simplicity of differentiated cancers derived from thyroid follicular cells offers unique insights into how oncogenic drivers impact tumour phenotype. Essentially, the main oncoproteins in thyroid cancer activate nodes in the receptor tyrosine kinase–RAS–BRAF pathway, which constitutively induces MAPK signalling to varying degrees consistent with their specific biochemical mechanisms of action. The magnitude of the flux through the MAPK signalling pathway determines key elements of thyroid cancer biology, including differentiation state, invasive properties and the cellular composition of the tumour microenvironment. Progression of disease results from genomic lesions that drive immortalization, disrupt chromatin accessibility and cause cell cycle checkpoint dysfunction, in conjunction with a tumour microenvironment characterized by progressive immunosuppression. This Review charts the genomic trajectories of these common endocrine tumours, while connecting them to the biological states that they confer. In this Review, Fagin et al. outline the oncogenic drivers of the common endocrine tumours, which derive from thyroid follicular cells, and how these impact tumour phenotypes and disease progression.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 9","pages":"631-650"},"PeriodicalIF":78.5,"publicationDate":"2023-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10064004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-06DOI: 10.1038/s41568-023-00605-2
Anna Dart
Two independent studies published in Nature have collectively addressed the long-standing question of sex bias in cancer and implicated non-hormonal genes of the Y chromosome in aggressive features of colorectal and bladder cancers in men.
发表在《自然》（Nature）杂志上的两项独立研究共同探讨了癌症中长期存在的性别偏见问题，并指出 Y 染色体的非激素基因与男性结直肠癌和膀胱癌的侵袭性特征有关。
{"title":"The Y chromosome as a risk factor","authors":"Anna Dart","doi":"10.1038/s41568-023-00605-2","DOIUrl":"10.1038/s41568-023-00605-2","url":null,"abstract":"Two independent studies published in Nature have collectively addressed the long-standing question of sex bias in cancer and implicated non-hormonal genes of the Y chromosome in aggressive features of colorectal and bladder cancers in men.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 8","pages":"511-511"},"PeriodicalIF":78.5,"publicationDate":"2023-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9876449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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