Evolutionary trajectories of small cell lung cancer under therapy
Julie George, Lukas Maas, Nima Abedpour, Maria Cartolano, Laura Kaiser, Rieke Fischer, Andreas H. Scheel, Jan-Philipp Weber, Martin Hellmich, Graziella Bosco, Caroline Volz, Christian Mueller, Ilona Dahmen, Felix John, Cleidson P. Alves, Lisa Werr, Jens Panse, Martin Kirschner, Walburga Engel-Riedel, Jessica Jürgens, Erich Stoelben, Michael Brockmann, Stefan Grau, Martin Sebastian, Jan Stratmann, Jens Kern, Horst-Dieter Hummel, Balázs Hegedűs, Martin Schüler, Till Plönes, Clemens Aigner, Thomas Elter, Karin Toepelt, Yon‐Dschun Ko, S Kurz, Christian Grohé, Monika Serke, Katja Höpker, Lars Hagmeyer, Fabian Doerr, Khosro Hekmath, Judith Strapatsas, K Kambartel, Geothy Chakupurakal, Annette Busch, Franz‐Georg Bauernfeind, Frank Griesinger, Anne Luers, Wiebke Dirks, Rainer Wiewrodt, Andrea Luecke, Ernst Rodermann, Andreas Diel, Volker Hagen, K. Severin, Roland T. Ullrich, Hans Christian Reinhardt, Alexander Quaas, Magdalena Bogus, Cornelius Courts, Peter Nürnberg, Kerstin Becker, Viktor Achter, Reinhard Büttner, Jürgen Wolf, Martin Peifer, Roman K. Thomas
Abstract
. 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.