Progress on the role of extrachromosomal <scp>DNA</scp> in tumor pathogenesis and evolution

Xing, Jichen; Ning, Qian; Tang, Dongxing; Zhang, Mo; Lei, Xiaoyong; Tang, Shengsong

doi:10.1111/cge.13896

Cited by 8 publications

(4 citation statements)

References 88 publications

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“…Using our cell line model, we further discover that ecDNA can provide more elevated copy numbers than HSR due to the lack of a centromere leading to unequal segregation at cell division, suggesting a more pivotal role of ecDNA in adapting to selective pressures from cancer therapy. Previous studies have shown that ecDNA may dynamically relocate to chromosomal HSR [ 5 , 33 ]. Other studies also found that HSR may promote the formation of ecDNA [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance

Meng,

Ma,

Liu

et al. 2024

Br J Cancer

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Background Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. Methods We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. Results The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. Conclusion The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

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Section: Discussionmentioning

confidence: 99%

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance

Meng,

Ma,

Liu

et al. 2024

Br J Cancer

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“…The behavior and structure of ecDNAs are different between various cancer types [ 94 , 95 ]. EcDNAs lead to tumor heterogeneity and drug resistance by promoting the amplification of oncogenes [ 96 , 97 , 98 , 99 , 100 ].…”

Section: Intratumoral Heterogeneitymentioning

confidence: 99%

Unraveling the Impact of Intratumoral Heterogeneity on EGFR Tyrosine Kinase Inhibitor Resistance in EGFR-Mutated NSCLC

Kobayashi

Tan

2023

IJMS

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The advent of tyrosine kinase inhibitors (TKIs) for treating epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) has been a game changer in lung cancer therapy. However, patients often develop resistance to the drugs within a few years. Despite numerous studies that have explored resistance mechanisms, particularly in regards to collateral signal pathway activation, the underlying biology of resistance remains largely unknown. This review focuses on the resistance mechanisms of EGFR-mutated NSCLC from the standpoint of intratumoral heterogeneity, as the biological mechanisms behind resistance are diverse and largely unclear. There exist various subclonal tumor populations in an individual tumor. For lung cancer patients, drug-tolerant persister (DTP) cell populations may have a pivotal role in accelerating the evolution of tumor resistance to treatment through neutral selection. Cancer cells undergo various changes to adapt to the new tumor microenvironment caused by drug exposure. DTP cells may play a crucial role in this adaptation and may be fundamental in mechanisms of resistance. Intratumoral heterogeneity may also be precipitated by DNA gains and losses through chromosomal instability, and the role of extrachromosomal DNA (ecDNA) may play an important role. Significantly, ecDNA can increase oncogene copy number alterations and enhance intratumoral heterogeneity more effectively than chromosomal instability. Additionally, advances in comprehensive genomic profiling have given us insights into various mutations and concurrent genetic alterations other than EGFR mutations, inducing primary resistance in the context of tumor heterogeneity. Understanding the mechanisms of resistance is clinically crucial since these molecular interlayers in cancer-resistance mechanisms may help to devise novel and individualized anticancer therapeutic approaches.

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“…Although its significance is rapidly gaining recognition, the role of extrachromosomal DNA (ecDNA)—circular DNA constructed from nucleosomal chromatin—in cancer is less well characterized. ecDNA has been identified as a major carrier of amplified oncogenes ( 1 ), and it is more open than chromosomal DNA, resulting in increased transcriptional activity ( 2 ). Owing to its lack of a centromere, ecDNA is inherited in a non-Mendelian pattern during mitosis ( 3 ), resulting in some tumour cells carrying high copy numbers of oncogenes that can substantially influence tumor heterogeneity and drug resistance ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Extrachromosomal DNA (ecDNA) in cancer: mechanisms, functions, and clinical implications

Dong

Chen

et al. 2023

Front. Oncol.

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Extrachromosomal DNA (ecDNA) is circular DNA that plays an important role in the development and heterogeneity of cancer. The rapid evolution of methods to detect ecDNA, including microscopic and sequencing approaches, has greatly enhanced our knowledge of the role of ecDNA in cancer development and evolution. Here, we review the molecular characteristics, functions, mechanisms of formation, and detection methods of ecDNA, with a focus on the potential clinical implications of ecDNA in cancer. Specifically, we consider the role of ecDNA in acquired drug resistance, as a diagnostic and prognostic biomarker, and as a therapeutic target in the context of cancer. As the pathological and clinical significance of ecDNA continues to be explored, it is anticipated that ecDNA will have broad applications in the diagnosis, prognosis, and treatment of patients with cancer.

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Progress on the role of extrachromosomal DNA in tumor pathogenesis and evolution

Cited by 8 publications

References 88 publications

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance

Unraveling the Impact of Intratumoral Heterogeneity on EGFR Tyrosine Kinase Inhibitor Resistance in EGFR-Mutated NSCLC

Extrachromosomal DNA (ecDNA) in cancer: mechanisms, functions, and clinical implications

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