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George, Julie; Maas, Lukas; Abedpour, Nima; Cartolano, Maria; Kaiser, Laura; Fischer, Rieke N.; Scheel, Andreas H.; Weber, Jan-Philipp; Hellmich, Martin; Bosco, Graziella; Volz, Caroline; Mueller, Christian; Dahmen, Ilona; John, Felix; Alves, Cleidson Padua; Werr, Lisa; Panse, Jens Peter; Kirschner, Martin; Engel-Riedel, Walburga; Jürgens, Jessica; Stoelben, Erich; Brockmann, Michael; Grau, Stefan; Sebastian, Martin; [...]

Evolutionary trajectories of small cell lung cancer under therapy

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  • Medientyp: E-Artikel
  • Titel: Evolutionary trajectories of small cell lung cancer under therapy
  • Beteiligte: George, Julie; Maas, Lukas; Abedpour, Nima; Cartolano, Maria; Kaiser, Laura; Fischer, Rieke N.; Scheel, Andreas H.; Weber, Jan-Philipp; Hellmich, Martin; Bosco, Graziella; Volz, Caroline; Mueller, Christian; Dahmen, Ilona; John, Felix; Alves, Cleidson Padua; Werr, Lisa; Panse, Jens Peter; Kirschner, Martin; Engel-Riedel, Walburga; Jürgens, Jessica; Stoelben, Erich; Brockmann, Michael; Grau, Stefan; Sebastian, Martin; [...]
  • Erschienen: Springer Science and Business Media LLC, 2024
  • Erschienen in: Nature
  • Sprache: Englisch
  • DOI: 10.1038/s41586-024-07177-7
  • ISSN: 0028-0836; 1476-4687
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown<jats:sup>1–3</jats:sup>. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas <jats:italic>TP53</jats:italic> and <jats:italic>RB1</jats:italic> alterations were exclusively part of the common ancestor, <jats:italic>MYC</jats:italic> family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal <jats:italic>CREBBP</jats:italic>/<jats:italic>EP300</jats:italic> alterations underwent genome duplications. Gene-damaging <jats:italic>TP53</jats:italic> alterations and co-alterations of <jats:italic>TP53</jats:italic> missense mutations with <jats:italic>TP73</jats:italic>, <jats:italic>CREBBP</jats:italic>/<jats:italic>EP300</jats:italic> or <jats:italic>FMN2</jats:italic> were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.</jats:p>