Paul S. Mischel

Nov 6, 2024 | nature.com | Oriol Pich |Kerstin Thol |Jens Luebeck |Natasha E. Weiser |Wei-Ting Lu |Brooke E. Howitt | +11 more

AbstractExtrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer1,2. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA.

Nov 6, 2024 | nature.com | L. T. Hung |Britney Jiayu He |Jens Luebeck |Lotte Brückner |Xiaowei Yan |Rocio Gonzalez | +8 more

AbstractThe chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently1. Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division2,3. Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells4.

Feb 26, 2024 | nature.com | Xiaowei Yan |Paul S. Mischel |Howard Chang

AbstractExtrachromosomal DNA (ecDNA) has recently been recognized as a major contributor to cancer pathogenesis that is identified in most cancer types and is associated with poor outcomes. When it was discovered over 60 years ago, ecDNA was considered to be rare, and its impact on tumour biology was not well understood. The application of modern imaging and computational techniques has yielded powerful new insights into the importance of ecDNA in cancer.

Nov 9, 2023 | nature.com | Meghana S. Pagadala |Jon Larson |L. T. Hung |Nicole G. Coufal |Howard Chang |Jesse R. Dixon | +8 more

AbstractCircular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%).

Jun 7, 2023 | nature.com | Albert S Agustinus |Stephanie Stransky |Lorenzo Scipioni |Jens Luebeck |Robert Myers |Britta Weigelt | +13 more

AbstractChromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1,2,3,4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells.