DNA damage refers to the permanent alteration of nucleotide sequences during DNA replication,leading to modifications in genetic characteristics.Cells can rectify the majority of such damage through DNA damage repair(...DNA damage refers to the permanent alteration of nucleotide sequences during DNA replication,leading to modifications in genetic characteristics.Cells can rectify the majority of such damage through DNA damage repair(DDR)mechanisms-including base excision repair(BER),nucleotide excision repair(NER),mismatch repair(MMR),homologous recombination(HR),canonical non-homologous end joining(NHEJ),and alternative non-homologous end joining(alt-NHEJ)-thereby maintaining genomic stability.1 Extrachromosomal DNA(ecDNA)refers to circular DNA molecules existing outside chromosomes,which have been demonstrated to play a critical role in tumor progression and evolution.2 EcDNA has been considered a marker of genomic instability,as ecDNA-positive tumors have been found to exhibit elevated DNA replication stress and higher levels of DNA double-strand breaks(DSBs).3 However,the precise relationship between ecDNA and the DDR,as well as the specific mechanisms governing ecDNA replication and maintenance,remains to be elucidated.展开更多
Extrachromosomal DNA(ecDNA)drives the evolution of cancer cells.Its widespread presence in tumors and strong association with poor clinical outcomes make ecDNA a promising and broadly applicable therapeutic target.Rec...Extrachromosomal DNA(ecDNA)drives the evolution of cancer cells.Its widespread presence in tumors and strong association with poor clinical outcomes make ecDNA a promising and broadly applicable therapeutic target.Recent studies have begun to unravel the mechanisms by which ecDNA promotes tumorigenesis and maintains its presence in cancer cells.These discoveries have paved the way for developing ecDNA-targeted therapies.In this Perspective,we summarize the latest advances in our understanding of the mechanism underlying both the ecDNA-induced cancer phenotype and ecDNA maintenance.We also explore potential strategies for targeting ecDNA in cancer treatment.展开更多
1 Main text,In a recent study,Shixiang Wang and colleagues developed a machine learning-based computational framework called GCAP to detect ecDNA amplification directly from whole-exome sequencing(WES)data,and reveale...1 Main text,In a recent study,Shixiang Wang and colleagues developed a machine learning-based computational framework called GCAP to detect ecDNA amplification directly from whole-exome sequencing(WES)data,and revealed clinical implications of ecDNA in TCGA pancancer study,colorectal cancer subtyping and immunotherapy response[1].In this commentary,we highlight the key findings and provide our insights into paradigm for real-world clinical ecDNA cancer investigation,as well as potential alterations in commentary for tumor diagnostics and therapy strategy(Fig.1).展开更多
Pradella et al.[1]recently published their latest research in Nature,reporting successful focal gene amplification in primary cells and organisms by engineering extrachromosomal DNA(ecDNA),confirming for the first tim...Pradella et al.[1]recently published their latest research in Nature,reporting successful focal gene amplification in primary cells and organisms by engineering extrachromosomal DNA(ecDNA),confirming for the first time the direct promotion of ecDNA in tumorigenesis and further uncovering how malignant cells acquire the uncontrolled function of the MDM2 and MYC.展开更多
Hepatitis B virus(HBV)is the most common cause of hepatocellular carcinoma(HCC),which is the predominant liver cancer type in Southeast Asia.Approximately 350 million individuals suffer from persistent hepatitis B inf...Hepatitis B virus(HBV)is the most common cause of hepatocellular carcinoma(HCC),which is the predominant liver cancer type in Southeast Asia.Approximately 350 million individuals suffer from persistent hepatitis B infection worldwide.HBV promotes HCC development through direct and indirect mechanisms.HBV DNA integrates into the host genome during the initial stages of tumorigenesis,causing insertional mutagenesis of cancer-related genes and genomic instability.Extrachromosomal circular DNA(ecDNA)is formed,which is efficiently amplified in large quantities to express viral genes and host oncogenes.Moreover,virus-associated proteins,such as the regulatory HBV X(HBx)protein and/or the modified preS/S envelope protein,alter the expression of genes associated with multiple functions in host cells.In this review,we summarize the role of the HBx and preS/S proteins in promoting tumorigenesis.In addition to summarizing the specific mechanism of HBV-related tumorigenesis,the concerns and perspectives for future study are discussed.展开更多
文摘DNA damage refers to the permanent alteration of nucleotide sequences during DNA replication,leading to modifications in genetic characteristics.Cells can rectify the majority of such damage through DNA damage repair(DDR)mechanisms-including base excision repair(BER),nucleotide excision repair(NER),mismatch repair(MMR),homologous recombination(HR),canonical non-homologous end joining(NHEJ),and alternative non-homologous end joining(alt-NHEJ)-thereby maintaining genomic stability.1 Extrachromosomal DNA(ecDNA)refers to circular DNA molecules existing outside chromosomes,which have been demonstrated to play a critical role in tumor progression and evolution.2 EcDNA has been considered a marker of genomic instability,as ecDNA-positive tumors have been found to exhibit elevated DNA replication stress and higher levels of DNA double-strand breaks(DSBs).3 However,the precise relationship between ecDNA and the DDR,as well as the specific mechanisms governing ecDNA replication and maintenance,remains to be elucidated.
基金National Key R&D Program of China(2023YFA0913400)National Natural Science Foundation of China(32525019)+4 种基金Shenzhen Medical Research Fund(B2302049)Major Program of the National Natural Science Foundation of China(32090031)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0480000)Guangdong Provincial Key Laboratory of Synthetic Genomics(2023B1212060054)Shenzhen Key Laboratory of Synthetic Genomics(ZDSYS201802061806209)。
文摘Extrachromosomal DNA(ecDNA)drives the evolution of cancer cells.Its widespread presence in tumors and strong association with poor clinical outcomes make ecDNA a promising and broadly applicable therapeutic target.Recent studies have begun to unravel the mechanisms by which ecDNA promotes tumorigenesis and maintains its presence in cancer cells.These discoveries have paved the way for developing ecDNA-targeted therapies.In this Perspective,we summarize the latest advances in our understanding of the mechanism underlying both the ecDNA-induced cancer phenotype and ecDNA maintenance.We also explore potential strategies for targeting ecDNA in cancer treatment.
文摘染色体外DNA(extrachromosomal DNA,ecDNA)是位于染色体外的环状DNA,存在于人类肿瘤细胞中,与人类肿瘤的发生发展相关。染色体外DNA含有多个完整的基因和调节转录的调节区,包括启动子和增强子,可以独立完成复制,其形成机制仍不明确。大多学者认为,DNA损伤会导致染色体外DNA的产生。由于DNA双链断裂(double-strand breaks,DSB)产生碎裂的染色体片段,通过非同源末端连接(non-homologous end joining,NHEJ)将这些片段重新排列,或环状连接而产生染色体外DNA。染色体外DNA的染色质具有高度可及性和活跃性;染色体外DNA上的增强子与癌基因共扩增,并对癌基因的转录起促进作用;染色体外DNA上可发生超远距离的染色质接触,从而对远距离的基因进行调控。以上因素促使染色体外DNA上的癌基因大量表达,最终促进癌症的发生发展。染色体外DNA缺乏着丝粒,使其不均等分离至子细胞,不仅使子细胞获得不同拷贝数量的染色体外DNA,还有利于获得更多染色体外DNA的细胞更快获得高拷贝数量的癌基因,导致肿瘤细胞的基因组异质性。同时,肿瘤通过染色体外DNA调节基因拷贝数,可使肿瘤逃避药物作用,从而使肿瘤产生耐药性,并能更好地适应环境的变化。本文主要综述染色体外DNA的分类、形成机制及其在肿瘤发生发展中的作用,讨论染色体外DNA促使肿瘤细胞高表达癌基因及其导致肿瘤细胞异质性和耐药性的机制,旨在为肿瘤的诊断、治疗及预后提供新思路。
基金supported by following fundings:Beijing Natural Science Foundation(Grant No.JQ24045)Capital's Funds for Health Improvement and Research(Grant No.2024-2-40211)+3 种基金Beijing Nova Program(Grant No.20220484210).Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-JKCS-07)Beijing Hope Run Special Fund of Cancer Foundation of China(LC2022L02)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-066)CAMS Innovation Fund for Medical Sciences(CIFMS)(2023-I2M-C&T-B-083).
文摘1 Main text,In a recent study,Shixiang Wang and colleagues developed a machine learning-based computational framework called GCAP to detect ecDNA amplification directly from whole-exome sequencing(WES)data,and revealed clinical implications of ecDNA in TCGA pancancer study,colorectal cancer subtyping and immunotherapy response[1].In this commentary,we highlight the key findings and provide our insights into paradigm for real-world clinical ecDNA cancer investigation,as well as potential alterations in commentary for tumor diagnostics and therapy strategy(Fig.1).
基金supported by the National Natural Science Foundation of China(82201594 and 81502582)the Open project of State Key Laboratory of Animal Biotech Breeding(2025SKLAB6-13)the Construction Project of Liaoning Provincial Key Laboratory(2022JH13/10200026).
文摘Pradella et al.[1]recently published their latest research in Nature,reporting successful focal gene amplification in primary cells and organisms by engineering extrachromosomal DNA(ecDNA),confirming for the first time the direct promotion of ecDNA in tumorigenesis and further uncovering how malignant cells acquire the uncontrolled function of the MDM2 and MYC.
基金supported by the National Natural Science Foundation of China(grant numbers:81988101,82173146,U21A20376,82425038,and 82421005)the Natural Science Foundation of Shanghai(grant numbers:22140901000 and 21XD1404600)the National Key R&D Program of China(grant numbers:2023YFC2507500).
文摘Hepatitis B virus(HBV)is the most common cause of hepatocellular carcinoma(HCC),which is the predominant liver cancer type in Southeast Asia.Approximately 350 million individuals suffer from persistent hepatitis B infection worldwide.HBV promotes HCC development through direct and indirect mechanisms.HBV DNA integrates into the host genome during the initial stages of tumorigenesis,causing insertional mutagenesis of cancer-related genes and genomic instability.Extrachromosomal circular DNA(ecDNA)is formed,which is efficiently amplified in large quantities to express viral genes and host oncogenes.Moreover,virus-associated proteins,such as the regulatory HBV X(HBx)protein and/or the modified preS/S envelope protein,alter the expression of genes associated with multiple functions in host cells.In this review,we summarize the role of the HBx and preS/S proteins in promoting tumorigenesis.In addition to summarizing the specific mechanism of HBV-related tumorigenesis,the concerns and perspectives for future study are discussed.
