Evolutionary trajectories of small cell lung cancer under therapy

• 成果类型: Article
• 署名作者: 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; Juergens, Jessica; Stoelben, Erich; Brockmann, Michael; Grau, Stefan; Sebastian, Martin; Stratmann, Jan A.; Kern, Jens; Hummel, Horst-Dieter; Hegedues, Balazs; Schuler, Martin; Ploenes, Till; Aigner, Clemens; Elter, Thomas; Toepelt, Karin; Ko, Yon-Dschun; Kurz, Sylke; Grohe, Christian; Serke, Monika; Hoepker, Katja; Hagmeyer, Lars; Doerr, Fabian; Hekmath, Khosro; Strapatsas, Judith; Kambartel, Karl-Otto; Chakupurakal, Geothy; Busch, Annette; Bauernfeind, Franz-Georg; Griesinger, Frank; Luers, Anne; Dirks, Wiebke; Wiewrodt, Rainer; Luecke, Andrea; Rodermann, Ernst; Diel, Andreas; Hagen, Volker; Severin, Kai; Ullrich, Roland T.; Reinhardt, Hans Christian; Quaas, Alexander; Bogus, Magdalena; Courts, Cornelius; Nuernberg, Peter; Becker, Kerstin; Achter, Viktor; Buettner, Reinhard; Wolf, Juergen; Peifer, Martin; Thomas, Roman K.
• 署名单位: University of Cologne; University of Cologne; University of Cologne; University of Cologne; University of Cologne; University of Cologne; University of Cologne; University of Cologne; RWTH Aachen University; RWTH Aachen University Hospital; University of Cologne; University of Cologne; Goethe University Frankfurt; Goethe University Frankfurt Hospital; Goethe University Frankfurt; Helmholtz Association; German Cancer Research Center (DKFZ); University of Wurzburg; University of Duisburg Essen; University of Duisburg Essen; Technische Universitat Dresden; Carl Gustav Carus University Hospital; Medical University of Vienna; University of Cologne; University of Cologne; University of Bonn; Pius-Hospital Oldenburg; University of Munster; St. Johannes Hospital; University of Duisburg Essen; University of Duisburg Essen; University of Cologne; University of Cologne; University of Cologne
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6404
• DOI: 10.1038/s41586-024-07177-7
• 发表日期: 2024-03-28
• 关键词: mutational signatures; genome; Heterogeneity; HISTORY; relapse

摘要

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. 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 TP53 and RB1 alterations were exclusively part of the common ancestor, MYC 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 CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 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. We uncover key processes of the genomic evolution of small cell lung cancer under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with drug response.